bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–10–20
79 papers selected by
Henver Brunetta, Karolinska Institutet
  1. Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.
  2. Impacts of time-restricted feeding on middle-aged and old mice with obesity.
  3. The SIRT5-Mediated Upregulation of C/EBPβ Promotes White Adipose Tissue Browning by Enhancing UCP1 Signaling.
  4. Quantification of nutrient fluxes during acute exercise in mice.
  5. Fatty acids promote uncoupled respiration via the ATP/ADP carrier in white adipocytes.
  6. Low-intensity pulsed ultrasound improves metabolic dysregulation in obese mice by suppressing inflammation and extracellular matrix remodeling.
  7. Luteolin alleviates muscle atrophy, mitochondrial dysfunction and abnormal FNDC5 expression in high fat diet-induced obese rats and palmitic acid-treated C2C12 myotubes.
  8. Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.
  9. Molecular mechanisms of mitochondrial dynamics.
  10. Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
  11. MICUs protect the heart by regulating mitochondrial calcium.
  12. Optogenetic Control of the Mitochondrial Protein Import in Mammalian Cells.
  13. Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects.
  14. Heart Failure and Obesity: Unraveling Molecular Mechanisms of Excess Adipose Tissue.
  15. Tip60-mediated Rheb acetylation links palmitic acid with mTORC1 activation and insulin resistance.
  16. Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.
  17. Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
  18. Irisin improves ROS‑induced mitohormesis imbalance in H9c2 cells.
  19. Association of epicardial fat with cardiac structure and function and exercise capacity in heart failure with preserved ejection fraction: A systematic review and meta-analysis.
  20. Sustained caloric restriction potentiates insulin action by activating prostacyclin synthase.
  21. MPV17 Prevents Myocardial Ferroptosis and Ischemic Cardiac Injury through Maintaining SLC25A10-Mediated Mitochondrial Glutathione Import.
  22. A simulation study on the role of mitochondria-sarcoplasmic reticulum Ca2+ interaction in cardiomyocyte energetics during exercise.
  23. Low serum glycine strengthens the association between branched-chain amino acids and impaired insulin sensitivity assessed before and after weight loss in a population with pre-diabetes: The PREVIEW_NZ cohort.
  24. Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock.
  25. Short-term intermittent fasting and energy restriction do not impair rates of muscle protein synthesis: A randomised, controlled dietary intervention.
  26. Inhibiting glycosphingolipids alleviates cardiac hypertrophy by reducing reactive oxygen species and restoring autophagic homeostasis.
  27. Epicardial adipose tissue and exercise intolerance in HFpEF.
  28. Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction.
  29. Cross-Species Studies Reveal That Dysregulated Mitochondrial Gene Expression and Electron Transport Complex I Activity Are Crucial for Sarcopenia.
  30. Visualizing VDAC1 in live cells using a tetracysteine tag.
  31. The Oldest of Old Male C57B/6J Mice Are Protected from Sarcopenic Obesity: The Possible Role of Skeletal Muscle Protein Kinase B Expression.
  32. Photobiomodulation Enhances the Effect of Strength Training on Insulin Resistance Regardless of Exercise Volume in Mice Fed a High-Fat Diet.
  33. Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response.
  34. Alpha Hydroxyl Acids from Mume Fructus and Schisandrae Chinensis Fructus Prevent Obesity by Inhibiting Intestinal Lipase in Diet-Induced Obese Mice.
  35. miR-210 as a therapeutic target in diabetes-associated endothelial dysfunction.
  36. Impaired Suppression of Plasma Lipid Extraction and its Partitioning Away from Muscle by Insulin in Humans with Obesity.
  37. Normobaric hypoxia accelerates high-intensity intermittent training-induced mitochondrial biogenesis (PGC-1α)- and dynamics (OPA1)-related protein expressions in rat gastrocnemius muscle.
  38. Modulators of Energy Expenditure Accuracy in Adults with Overweight or Obesity: E-MECHANIC Secondary Analyses.
  39. Limitations in metabolic plasticity after traumatic injury are only moderately exacerbated by physical activity restriction.
  40. Pharmacological inhibition reveals participation of the endocytic compartment in positive feedback IL-6 secretion in human skeletal myotubes.
  41. Apoptosis-induced translocation of nesprin-2 from the nuclear envelope to mitochondria is associated with mitochondrial dysfunction.
  42. The Novel Anticancer Aryl-Ureido Fatty Acid CTU Increases Reactive Oxygen Species Production That Impairs Mitochondrial Fusion Mechanisms and Promotes MDA-MB-231 Cell Death.
  43. Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes.
  44. Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione's in fructose induced insulin resistant rats.
  45. Profiling Reduced Expression of Contractile and Mitochondrial mRNAs in the Human Sinoatrial Node vs. Right Atrium and Predicting Their Suppressed Expression by Transcription Factors and/or microRNAs.
  46. Structural basis of respiratory complex adaptation to cold temperatures.
  47. An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.
  48. Myosteatosis and sarcopenia are linked to autonomous cortisol secretion in patients with aldosterone-producing adenomas.
  49. PFKP inhibition protects against pathological cardiac hypertrophy by regulating protein synthesis.
  50. Analyzing Mitochondrial Calcium Influx in Isolated Mitochondria.
  51. The Downregulation of the Liver Lipid Metabolism Induced by Hypothyroidism in Male Mice: Metabolic Flexibility Favors Compensatory Mechanisms in White Adipose Tissue.
  52. GQ262 Attenuates Pathological Cardiac Remodeling by Downregulating the Akt/mTOR Signaling Pathway.
  53. Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα-TRAF3-TAK1-MAPK axis.
  54. Improvement of heart rate variability after metabolic bariatric surgery in Korean subjects with obesity.
  55. The heart is a muscle: on-call fitness guide for the busy cardiovascular surgeon and interventionalist.
  56. Suppressed ORAI1-STIM1-dependent Ca2+ entry by protein kinase C isoforms regulating platelet procoagulant activity.
  57. Multi-Omics Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.
  58. Daucosterol alleviates heart failure with preserved ejection fraction through activating PPARα pathway.
  59. Management of Left Atrial Tachyrhythms in the Setting of HFpEF with Pulsed-Field Ablation: Treating Fire with Water?
  60. NBF2, an Algal Fiber-Rich Formula, Reverses Diabetic Dyslipidemia and Hyperglycemia In Vivo.
  61. Nutritional deuterium depletion and health: a scoping review.
  62. Metabolic pathways for removing reactive aldehydes are diminished in the skeletal muscle during heart failure.
  63. Skeletal muscle fuel utilisation during exercise: A historical account of the Scandinavian involvement in the 'Zuntz-Chauveau controversy'.
  64. Associations of artificial sweetener intake with cardiometabolic disorders and mortality: a population-based study.
  65. Heart Failure with Preserved Ejection Fraction Correlates with Fibrotic Atrial Myopathy in Patients Undergoing Atrial Fibrillation Ablation.
  66. Hyperglycemia-depleted glutamine contributes to the pathogenesis of diabetic corneal endothelial dysfunction.
  67. Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target?
  68. Readdressing the Localization of Apolipoprotein E (APOE) in Mitochondria-Associated Endoplasmic Reticulum (ER) Membranes (MAMs): An Investigation of the Hepatic Protein-Protein Interactions of APOE with the Mitochondrial Proteins Lon Protease (LONP1), Mitochondrial Import Receptor Subunit TOM40 (TOMM40) and Voltage-Dependent Anion-Selective Channel 1 (VDAC1).
  69. Quantifying constraint in the human mitochondrial genome.
  70. Cardiac structural and functional changes in OSAHS patients with heart failure with preserved ejection fraction and atrial fibrillation.
  71. Metabolic kinetics and muscle and brain health markers in older adults, and the role of age and presence of chronic morbidities: A large cross-sectional cohort study.
  72. The integrative biology of the heart: mechanisms enabling cardiac plasticity.
  73. Alterations in cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation.
  74. Low-calorie, high-protein diets, regardless of protein source, improve glucose metabolism and cardiometabolic profiles in subjects with prediabetes or type 2 diabetes and overweight or obesity.
  75. Protein kinase 2 of the giant sarcomeric protein UNC-89 regulates mitochondrial morphology and function.
  76. Decoding visceral adipose tissue molecular signatures in obesity and insulin resistance: a multi-omics approach.
  77. Sphingomyelins of Local Fat Depots and Blood Serum as Promising Biomarkers of Cardiovascular Diseases.
  78. Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
  79. Sex differences in the relationship between body composition and cardiac structure and function.
  1. bioRxiv. 2024 Oct 08. pii: 2024.10.07.617073. [Epub ahead of print]
    Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.
    Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, Marisa J Lang, Luis Cedeño-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Ji Eon Kim, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, James Carrington, Jonathan Leon Catrow, Quentinn Pearce, Mi-Young Jeong, Alex J Bott, Álvaro J Narbona-Pérez, Claire E Stanley, Qing Li, David R Eberhardt, Jeffrey T Morgan, Tarun Yadav, Chloe E Wells, Dinesh K A Ramadurai, Wojciech I Swiatek, Dipayan Chaudhuri, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Steven A Baker, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.
      Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.
    DOI:  https://doi.org/10.1101/2024.10.07.617073
  2. J Physiol. 2024 Oct 15.
    Impacts of time-restricted feeding on middle-aged and old mice with obesity.
    Yueze Yang, Dexi Liu.
      Time-restricted feeding is known to ameliorate obesity in young mice. However, evaluation of its effect in old age is still lacking. The current work aims to investigate the effects of time-restricted feeding on treating pre-existing obesity in old animals. The study utilized middle-aged and old high fat diet-induced obese mice and subjected them to 8 h daily time-restricted feeding. Aged obese mice did not lose fat mass but lost lean mass after 8 weeks of treatment. In addition, time-restricted feeding reduced adiposity in brown adipose tissue, reversed excessive hepatic lipid accumulation, and improved glucose homeostasis in middle-aged and old obese mice. Mechanistic studies show that these metabolic benefits were mediated by transcriptional downregulation of essential genes responsible for hepatic adipogenesis and adipose tissue chronic inflammation. These results demonstrate that time-restricted feeding improves metabolic health and has beneficial effects in combating diet-induced obesity in aged obese mice. KEY POINTS: Contrary to in young obese mice, in old obese mice time-restricted feeding did not significantly reduce body fat but decreased lean mass. Time-restricted feeding reduced adipose tissue inflammation, reversed fatty liver, and improved glucose homeostasis in aged mice with diet-induced obesity. Time-restricted feeding is effective in improving metabolic homeostasis in aged mice, but less effective in terms of reducing obesity. Future studies should investigate the underlying mechanism of how ageing impaired intermittent fasting induced fat loss.
    Keywords:  ageing; fatty liver; insulin resistance; intermittent fasting; obesity; time‐restricted feeding
    DOI:  https://doi.org/10.1113/JP285462
  3. Int J Mol Sci. 2024 Sep 29. pii: 10514. [Epub ahead of print]25(19):
    The SIRT5-Mediated Upregulation of C/EBPβ Promotes White Adipose Tissue Browning by Enhancing UCP1 Signaling.
    Xiangyun Zhai, Liping Dang, Shiyu Wang, Chao Sun.
      Sirtuin 5 (SIRT5) plays an important role in the maintenance of lipid metabolism and in white adipose tissue browning. In this study, we established a mouse model for diet-induced obesity and the browning of white fat; combined with gene expression intervention, transcriptome sequencing, and cell molecular biology methods, the regulation and molecular mechanisms of SIRT5 on fat deposition and beige fat formation were studied. The results showed that the loss of SIRT5 in obese mice exacerbated white adipose tissue deposition and metabolic inflexibility. Furthermore, the deletion of SIRT5 in a white-fat-browning mouse increased the succinylation of uncoupling protein 1 (UCP1), resulting in a loss of the beiging capacity of the subcutaneous white adipose tissue and impaired cold tolerance. Mechanistically, the inhibition of SIRT5 results in impaired CCAAT/enhancer binding protein beta (C/EBPβ) expression in brown adipocytes, which in turn reduces the UCP1 transcriptional pathway. Thus, the transcription of UCP1 mediated by the SIRT5-C/EBPβ axis is critical in regulating energy balance and obesity-related metabolism.
    Keywords:  SIRT5; UCP1; fat synthesis; protein succinylation; white adipose tissue browning
    DOI:  https://doi.org/10.3390/ijms251910514
  4. Cell Metab. 2024 Oct 11. pii: S1550-4131(24)00374-7. [Epub ahead of print]
    Quantification of nutrient fluxes during acute exercise in mice.
    Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R Bornstein, Michael D Neinast, Caroline R Bartman, Megan C Blair, Kristina Li, Chelsea Thorsheim, Joshua D Rabinowitz, Zoltan Arany.
      Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use in vivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.
    Keywords:  TCA cycle; circulating metabolites; energy metabolism; exercise; in vivo flux quantification; isotope tracing; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.010
  5. Res Sq. 2024 Sep 25. pii: rs.3.rs-5094089. [Epub ahead of print]
    Fatty acids promote uncoupled respiration via the ATP/ADP carrier in white adipocytes.
    Shannon Reilly, Ayla Aksu, Zane Zerbel, Preetveer Dhillon, Yosip Kelemen, Oluwafemi Gbayisomore, Serena Chen, Maryam Ahmadian.
      Adipocytes store energy as triglycerides, while mobilizing energy when needed via lipolysis. Triglyceride lipolysis releases fatty acids and glycerol into the circulation to fuel other tissues. However, a significant fraction of fatty acids released by lipolysis are retained within the white adipose tissue and handled by adipocytes. While some of these retained fatty acids are re-esterified in white adipocytes1-6, the a substantial amount undergo oxidative metabolism via a pathway regulated by the nongenomic effects of STAT37-10. Here we report that fatty acids promote uncoupled oxidative metabolism in white adipocytes via the ATP/ADP carrier, contributing to thermogenesis and cold tolerance in obese thermoneutral-adapted mice, independent of brown adipose tissue and muscle activity. Our results suggest that uncoupled respiration in white adipocytes significantly contributes to whole-body energy expenditure and could be a promising target for obesity treatment.
    DOI:  https://doi.org/10.21203/rs.3.rs-5094089/v1
  6. Ultrasonics. 2024 Oct 10. pii: S0041-624X(24)00251-8. [Epub ahead of print]145 107488
    Low-intensity pulsed ultrasound improves metabolic dysregulation in obese mice by suppressing inflammation and extracellular matrix remodeling.
    Min He, Hong Zhu, Jingsong Dong, Wenzhen Lin, Boyi Li, Ying Li, Dean Ta.
      Chronic inflammation in white adipose tissue is crucial in obesity and related metabolic disorders. Low-intensity pulsed ultrasound (LIPUS) is renowned for its anti-inflammatory effects as a non-invasive treatment, yet its precise role in obesity has been uncertain. Our study investigates the therapeutic effect of LIPUS and its underlying mechanism on obesity in mice, thereby offering a novel approach for non-invasive treatment of obesity and associated metabolic disorders for human. Male C57BL/6J mice aged 10 weeks were fed a high-fat diet (HFD) for 8 weeks to establish obesity model, then underwent 8 weeks of LIPUS (frequency: 1.0 MHz, duty cycle: 20 %, Isata: 58-61 mW/cm2, 20 min per day) stimulation of the epididymal white adipose tissue. Fat and lean mass were measured using nuclear magnetic resonance (NMR), while energy homeostasis was evaluated using metabolic cages. Insulin resistance was assessed using glucose tolerance tests (GTT) and insulin tolerance tests (ITT). Regulatory mechanisms were explored using RNA sequencing. Results showed that LIPUS significantly reduced obesity markers in obese mice, including body and adipose tissue weight, and improved insulin resistance, without affecting food intake. RNA sequencing showed 250 up-regulated and 351 down-regulated genes between HFD-LIPUS group and HFD-Sham group, suggesting anti-inflammatory action. Quantitative PCR confirmed reduced pro-inflammatory gene expression and macrophage infiltration in eWAT. Gene set enrichment analysis showed decreased NF-κB signaling and extracellular matrix-receptor interactions in LIPUS-treated mice. Thus, LIPUS effectively mitigates metabolic dysregulation in HFD-induced obesity through inflammation suppression and extracellular matrix remodeling, which provides a potential physical therapy for metabolic syndrome in clinic.
    Keywords:  Adipose tissue; Inflammation; Insulin resistance; LIPUS; Obesity
    DOI:  https://doi.org/10.1016/j.ultras.2024.107488
  7. J Nutr Biochem. 2024 Oct 10. pii: S0955-2863(24)00211-0. [Epub ahead of print] 109780
    Luteolin alleviates muscle atrophy, mitochondrial dysfunction and abnormal FNDC5 expression in high fat diet-induced obese rats and palmitic acid-treated C2C12 myotubes.
    Yiyuan Zhang, Chunyun Luo, Puxin Huang, Yahong Cheng, Yufang Ma, Jiefang Gao, Hong Ding.
      Obesity is associated with a series of skeletal muscle impairments and dysfunctions, which are characterized by metabolic disturbances and muscle atrophy. Luteolin is a phenolic phytochemical with broad pharmacological activities. The present study aimed to evaluate the protective effects of Luteolin on muscle function and explore the potential mechanisms in high-fat diet (HFD)-induced obese rats and palmitic acid (PA)-treated C2C12 myotubes. Male Sprague-Dawley (SD) rats were fed with a control diet or HFD and orally administrated 0.5% sodium carboxymethyl cellulose (vehicle) or Luteolin (25, 50 and 100 mg/kg, respectively) for 12 weeks. The results showed that Luteolin ameliorated HFD-induced body weight gain, glucose intolerance and hyperlipidemia. Luteolin also alleviated muscle atrophy, decreased ectopic lipid deposition and prompted muscle-fiber-type conversion in the skeletal muscle. Meanwhile, we observed an evident improvement in mitochondrial quality control and respiratory capacity, accompanied by reduced oxidative stress. Mechanistic studies indicated that AMPK/SIRT1/PGC-1α signaling pathway plays a key role in the protective effects of Luteolin on skeletal muscle in the obese states, which was further verified by using specific inhibitors of AMPK and SIRT1. Moreover, the mRNA expression levels of markers in brown adipocyte formation were significantly up-regulated post Luteolin supplementation in different adipose depots. Taken together, these results revealed that Luteolin supplementation might be a promising strategy to prevent obesity-induced loss of mass and biological dysfunctions of skeletal muscle.
    Keywords:  Luteolin; high fat diet; irisin; mitochondrial dysfunction; muscle atrophy
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109780
  8. Circ Heart Fail. 2024 Oct 18. e011980
    Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.
    Senthil Selvaraj, Shachi Patel, Andrew J Sauer, Robert W McGarrah, Philip Jones, Lydia Coulter Kwee, Sheryl L Windsor, Olga Ilkayeva, Michael J Muehlbauer, Christopher B Newgard, Barry A Borlaug, Dalane W Kitzman, Sanjiv J Shah, Kenneth B Margulies, Mansoor Husain, Silvio E Inzucchi, Darren K McGuire, David E Lanfear, Ali Javaheri, Guillermo Umpierrez, Robert J Mentz, Kavita Sharma, Mikhail N Kosiborod, Svati H Shah.
       BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF.
    METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points.
    RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (Pinteraction>0.10), whereas the ketogenic effect diminished at higher LVEF (Pinteraction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF.
    CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes.
    REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.
    Keywords:  fatty acid; heart failure; ketone bodies; metabolomics; quality of life
    DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.011980
  9. Nat Rev Mol Cell Biol. 2024 Oct 17.
    Molecular mechanisms of mitochondrial dynamics.
    Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent.
      Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.
    DOI:  https://doi.org/10.1038/s41580-024-00785-1
  10. J Clin Invest. 2024 Oct 15. pii: e169722. [Epub ahead of print]
    Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
    Andrew LaPoint, Jason M Singer, Daniel Ferguson, Trevor M Shew, M Katie Renkemeyer, Hector H Palacios, Rachael L Field, Sireeesha Yerrathota, Roshan Kumari, Mahalakshmi Shankaran, Gordon I Smith, Jun Yoshino, Mai He, Gary J Patti, Marc K Hellerstein, Samuel Klein, E Matthew Morris, Jonathan R Brestoff, Brian N Finck, Andrew Lutkewitte.
      Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.
    Keywords:  Diabetes; Hepatology; Insulin signaling; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI169722
  11. Trends Pharmacol Sci. 2024 Oct 14. pii: S0165-6147(24)00209-8. [Epub ahead of print]
    MICUs protect the heart by regulating mitochondrial calcium.
    Ulas Ozkurede, Shanmugasundaram Pakkiriswami, Julia C Liu.
      Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter (mtCU) complex is crucial for heart function. In a recent study, Hasan et al. demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, providing potential targets for therapies aimed at improving mitochondrial function in heart disease.
    Keywords:  EMRE; MCU; MICU1; MICU2; calcium; heart; mitochondria
    DOI:  https://doi.org/10.1016/j.tips.2024.09.010
  12. Cells. 2024 Oct 09. pii: 1671. [Epub ahead of print]13(19):
    Optogenetic Control of the Mitochondrial Protein Import in Mammalian Cells.
    Lukas F J Althoff, Markus M Kramer, Benjamin Bührer, Denise Gaspar, Gerald Radziwill.
      Mitochondria provide cells with energy and regulate the cellular metabolism. Almost all mitochondrial proteins are nuclear-encoded, translated on ribosomes in the cytoplasm, and subsequently transferred to the different subcellular compartments of mitochondria. Here, we developed OptoMitoImport, an optogenetic tool to control the import of proteins into the mitochondrial matrix via the presequence pathway on demand. OptoMitoImport is based on a two-step process: first, light-induced cleavage by a TEV protease cuts off a plasma membrane-anchored fusion construct in close proximity to a mitochondrial targeting sequence; second, the mitochondrial targeting sequence preceding the protein of interest recruits to the outer mitochondrial membrane and imports the protein fused to it into mitochondria. Upon reaching the mitochondrial matrix, the matrix processing peptidase cuts off the mitochondrial targeting sequence and releases the protein of interest. OptoMitoImport is available as a two-plasmid system as well as a P2A peptide or IRES sequence-based bicistronic system. Fluorescence studies demonstrate the release of the plasma membrane-anchored protein of interest through light-induced TEV protease cleavage and its localization to mitochondria. Cell fractionation experiments confirm the presence of the peptidase-cleaved protein of interest in the mitochondrial fraction. The processed product is protected from proteinase K treatment. Depletion of the membrane potential across the inner mitochondria membrane prevents the mitochondrial protein import, indicating an import of the protein of interest by the presequence pathway. These data demonstrate the functionality of OptoMitoImport as a generic system with which to control the post-translational mitochondrial import of proteins via the presequence pathway.
    Keywords:  CRY2; LOV domain; MTS; TEV; matrix peptidases; mitochondrial import; optogenetics
    DOI:  https://doi.org/10.3390/cells13191671
  13. BMJ Open Diabetes Res Care. 2024 Oct 18. pii: e004199. [Epub ahead of print]12(5):
    Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects.
    Aurora Merovci, Brittany Finley, Andrea Hansis-Diarte, Sivaram Neppala, Muhammad A Abdul-Ghani, Eugenio Cersosimo, Curtis Triplitt, Ralph A DeFronzo.
       INTRODUCTION: Low carbohydrate ketogenic diets have received renewed interest for the treatment of obesity and type 2 diabetes. These diets promote weight loss, improve glycemic control, and reduce insulin resistance. However, whether the improvements in glycemic control and insulin sensitivity are secondary to the weight loss or result from a direct effect of hyperketonemia is controversial.
    RESEARCH DESIGN AND METHODS: 29 overweight obese subjects were randomized to one of three dietary interventions for 10 days: (1) Weight-maintaining standard diet; (2) Weight-maintaining ketogenic diet; (3) Weight-maintaining ketogenic diet plus supplementation with the ketone ester of beta-hydroxybutyrate (β-OH-B), 8 g every 8 hours. At baseline, all subjects had oral glucose tolerance test, 2-step euglycemic insulin clamp (20 mU/m2.min and 60 mU/m2.min) with titrated glucose and indirect calorimetry.
    RESULTS: Body weight, fat content, and per cent body fat (DEXA) remained constant over the 10-day dietary intervention period in all three groups. Plasma β-OH-B concentration increased twofold, while carbohydrate oxidation decreased, and lipid oxidation increased demonstrating the expected shifts in substrate metabolism with institution of the ketogenic diet. Glucose tolerance either decreased slightly or remained unchanged in the two ketogenic diet groups. Whole body (muscle), liver, and adipose tissue sensitivity to insulin remained unchanged in all 3 groups, as did the plasma lipid profile and blood pressure.
    CONCLUSION: In the absence of weight loss, a low carbohydrate ketogenic diet has no beneficial effect on glucose tolerance, insulin sensitivity, or other metabolic parameters.
    Keywords:  Diabetes Mellitus, Type 2; Diet; Ketones; Obesity
    DOI:  https://doi.org/10.1136/bmjdrc-2024-004199
  14. J Am Coll Cardiol. 2024 Oct 22. pii: S0735-1097(24)07905-1. [Epub ahead of print]84(17): 1666-1677
    Heart Failure and Obesity: Unraveling Molecular Mechanisms of Excess Adipose Tissue.
    Just Dronkers, Dirk J van Veldhuisen, Peter van der Meer, Laura M G Meems.
      Obesity is an ongoing pandemic and is associated with the development of heart failure (HF), and especially HF with preserved ejection fraction. The definition of obesity is currently based on anthropometric measurements but neglects the location and molecular properties of excess fat. Important depots associated with HF development are subcutaneous adipose tissue and visceral adipose tissue, both located in the abdominal region, and epicardial adipose tissue (EAT) surrounding the myocardium. However, mechanisms linking these different adipose tissue depots to HF development are incompletely understood. EAT in particular is of great interest because of its close proximity to the heart. In this review, we therefore focus on the characteristics of different adipose tissue depots and their response to obesity. In addition, we evaluate how different mechanisms associated with EAT expansion potentially contribute to HF and in particular HF with preserved ejection fraction development.
    Keywords:  adipose tissue; heart failure with preserved ejection fraction; molecular mechanisms; obesity
    DOI:  https://doi.org/10.1016/j.jacc.2024.07.016
  15. J Cell Biol. 2024 Dec 02. pii: e202309090. [Epub ahead of print]223(12):
    Tip60-mediated Rheb acetylation links palmitic acid with mTORC1 activation and insulin resistance.
    Zengqi Zhao, Qiang Chen, Xiaojun Xiang, Weiwei Dai, Wei Fang, Kun Cui, Baolin Li, Qiangde Liu, Yongtao Liu, Yanan Shen, Yueru Li, Wei Xu, Kangsen Mai, Qinghui Ai.
      Excess dietary intake of saturated fatty acids (SFAs) induces glucose intolerance and metabolic disorders. In contrast, unsaturated fatty acids (UFAs) elicit beneficial effects on insulin sensitivity. However, it remains elusive how SFAs and UFAs signal differentially toward insulin signaling to influence glucose homeostasis. Here, using a croaker model, we report that dietary palmitic acid (PA), but not oleic acid or linoleic acid, leads to dysregulation of mTORC1, which provokes systemic insulin resistance. Mechanistically, we show that PA profoundly elevates acetyl-CoA derived from mitochondrial fatty acid β oxidation to intensify Tip60-mediated Rheb acetylation, which triggers mTORC1 activation by promoting the interaction between Rheb and FKBPs. Subsequently, hyperactivation of mTORC1 enhances IRS1 serine phosphorylation and inhibits TFEB-mediated IRS1 transcription, inducing impairment of insulin signaling. Collectively, our results reveal a conserved molecular insight into the mechanism by which Tip60-mediated Rheb acetylation induces mTORC1 activation and insulin resistance under the PA condition, which may provide therapeutic avenues to intervene in the development of T2D.
    DOI:  https://doi.org/10.1083/jcb.202309090
  16. Adv Biol (Weinh). 2024 Oct 16. e2400235
    Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.
    Xin Zhang, Suchan Liao, Lingling Huang, Jinhua Wang.
      Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.
    Keywords:  Aging; mechanism; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1002/adbi.202400235
  17. Nat Metab. 2024 Oct 14.
    Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
    Ekaterina D Korobkina, Camila Martinez Calejman, John A Haley, Miranda E Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R Green, Paula Vo, Clay F Semenkovich, Jason R Pitarresi, Jessica B Spinelli, Ozkan Aydemir, Christian M Metallo, Matthew D Lynes, Cholsoon Jang, Nathaniel W Snyder, Kathryn E Wellen, David A Guertin.
      Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.
    DOI:  https://doi.org/10.1038/s42255-024-01143-3
  18. Mol Med Rep. 2024 Dec;pii: 240. [Epub ahead of print]30(6):
    Irisin improves ROS‑induced mitohormesis imbalance in H9c2 cells.
    Baogui Wang, Haibo Xu, Shuai Shang, Longxiang Liu, Chunlong Sun, Wen Du.
      Abnormal mitohormesis is a key pathogenic mechanism that induces a variety of cardiac diseases, including cardiac hypertrophy and heart failure. Irisin as a muscle factor serves a cardioprotective role in response to cellular oxidative stress injury. Rat cardiomyocyte cells (H9c2) were treated with 40 µM exogenous H2O2 to establish an oxidative stress model, followed by addition of 75 nM exogenous irisin for experiments to determine mitochondrial membrane potential, reactive oxygen species, and Mitohormesis‑related factors by attrition cytometry. Subsequently, the expression of mitochondrial membrane potential, reactive oxygen species and Mitohormesis‑related factors were continued to be determined by establishing a peroxisome proliferator‑activated receptor γ coactivator‑1 alpha (PGC‑1α) siRNA interference model and continuing the treatment with the addition of 75 nM irisin 12 h before the end of interference. When H9c2 cells underwent oxidative stress, irisin partially improved mitochondrial membrane potential and reactive oxygen species levels and partially restored mitochondrial energy metabolism by upregulating fusion proteins optic atrophy 1 (OPA1) mitochondrial dynamin‑like GTPase and mitofusin 2 and downregulating fission protein dynamin‑related protein 1. Following interference with PGC‑1α, irisin promoted mitochondrial biosynthesis by increasing the mRNA levels of OPA1 and protein levels of cytochrome c oxidase subunit 4. These results suggested that irisin acted partially independently of the PGC‑1α signaling pathway to regulate mitohormesis imbalance due to oxidative stress and maintain energy metabolism by improving mitochondrial structure.
    Keywords:  H9c2; PGC‑1α; irisin; mitohormesis; reactive oxygen species
    DOI:  https://doi.org/10.3892/mmr.2024.13364
  19. Int J Cardiol Heart Vasc. 2024 Oct;54 101444
    Association of epicardial fat with cardiac structure and function and exercise capacity in heart failure with preserved ejection fraction: A systematic review and meta-analysis.
    Hidekatsu Fukuta, Toshihiko Goto, Takeshi Kamiya.
       Background: Studies have reported the association of epicardial adipose tissue (EAT) with cardiac structure and function as well as exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF), yielding inconsistent results. We aimed to conduct a meta-analysis of studies on the association of EAT with cardiac structure and function and exercise capacity in HFpEF patients.
    Methods and Results: We searched studies examining the association of EAT quantified by echocardiography, computed tomography, or magnetic resonance imaging (MRI) with cardiac structure and function or exercise capacity in HFpEF patients through PubMed, Web of Science, and Scopus. In cases of significant heterogeneity (I2 > 50 %), data were pooled using a random-effects model; otherwise, a fixed-effects model was used. We identified five echocardiography studies (n = 825) and six MRI studies (n = 562), but found no computed tomography studies. In the echocardiography studies, EAT thickness correlated positively with left ventricular (LV) mass (P random  < 0.01) and negatively with LV global longitudinal strain (P random  < 0.01) and peak exercise oxygen uptake (P fix  < 0.001). In the MRI studies, EAT volume correlated positively with LV mass (P fix  < 0.01), left atrial volume (P fix  < 0.001), and the ratio of LV early diastolic mitral inflow to early diastolic mitral annular velocity (E/e'; P random  < 0.01) and negatively with LV ejection fraction (P fix  < 0.01) and LV global longitudinal strain (P fix  < 0.001).
    Conclusion: Our meta-analysis indicates a potential association of increased EAT with altered cardiac structure and function and exercise intolerance in HFpEF patients. However, our meta-analysis included only two or three studies for each outcome and thus further studies are necessary to confirm our findings.
    Keywords:  Adipose tissue; Epicardial fat; Heart failure; Meta-analysis; Preserved ejection fraction
    DOI:  https://doi.org/10.1016/j.ijcha.2024.101444
  20. Obesity (Silver Spring). 2024 Oct 17.
    Sustained caloric restriction potentiates insulin action by activating prostacyclin synthase.
    Carmen Merali, Connor Quinn, Kim M Huffman, Carl F Pieper, Jonathan S Bogan, Carlos A Barrero, Salim Merali.
       OBJECTIVE: Caloric restriction (CR) is known to enhance insulin sensitivity and reduce the risk of metabolic disorders; however, its molecular mechanisms are not fully understood. This study aims to elucidate specific proteins and pathways responsible for these benefits.
    METHODS: We examined adipose tissue from participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE 2) study, comparing proteomic profiles from individuals after 12 and 24 months of CR with baseline and an ad libitum group. Biochemical and cell-specific physiological approaches complemented these analyses.
    RESULTS: Our data revealed that CR upregulates prostacyclin synthase (PTGIS) in adipose tissue, an enzyme crucial for producing prostacyclin (PGI2). PGI2 improves the ability of insulin to stimulate the tether-containing UBX domain for GLUT4 (TUG) cleavage pathway, which is essential for glucose uptake regulation. Additionally, iloprost, a PGI2 analog, was shown to increase insulin receptor density on cell membranes, increasing glucose uptake in human adipocytes. CR also reduces carbonylation of GLUT4, a modification that is detrimental to GLUT4 function.
    CONCLUSIONS: CR enhances insulin sensitivity by promoting PTGIS expression and stimulating the TUG cleavage pathway, leading to increased GLUT4 translocation to the cell surface and decreased GLUT4 carbonylation. These findings shed light on the complex molecular mechanisms through which CR favorably impacts insulin sensitivity and metabolic health.
    DOI:  https://doi.org/10.1002/oby.24150
  21. Int J Mol Sci. 2024 Oct 09. pii: 10832. [Epub ahead of print]25(19):
    MPV17 Prevents Myocardial Ferroptosis and Ischemic Cardiac Injury through Maintaining SLC25A10-Mediated Mitochondrial Glutathione Import.
    Tao Xu, Guilan Chen.
      Ferroptosis is a recently identified iron-dependent programmed cell death with lipid peroxide accumulation and condensation and compaction of mitochondria. A recent study indicated that ferroptosis plays a pivotal role in ischemic cardiac injury with the mechanisms remain largely unknown. This study demonstrates that when an iron overload occurs in the ischemia/reperfusion cardiac tissues, which initiates myocardial ferroptosis, the expression levels of mitochondrial inner membrane protein MPV17 are reduced. Overexpression of MPV17 delivered via adenovirus significantly reduced ferroptosis in both cardiomyocytes with high levels of iron and cardiac I/R tissues. Mitochondrial glutathione (mtGSH), crucial for reactive oxygen species scavenging and mitochondrial homeostasis maintenance, is depleted in myocardial ferroptosis caused by iron overload. This mechanistic study shows that MPV17 can increase mitochondrial glutathione levels through maintaining the protein homeostasis of SLC25A10, which is a mitochondrial inner-membrane glutathione transporter. The absence of MPV17 in iron overload resulted in the ubiquitination-dependent degradation of SLC25A10, leading to impaired mitochondrial glutathione import. Moreover, we found that MPV17 was the targeted gene of Nrf2, which plays a pivotal role in preventing lipid peroxide accumulation and ferroptosis. The decreased expression levels of Nrf2 led to the inactivation of MPV17 in iron overload-induced myocardial ferroptosis. In summary, this study demonstrates the critical role of MPV17 in protecting cardiomyocytes from ferroptosis and elucidates the Nrf2-MPV17-SLC25A10/mitochondrial glutathione signaling pathway in the regulation of myocardial ferroptosis.
    Keywords:  MPV17; iron overload; ischemia/reperfusion injury; mitochondrial glutathione; myocardial ferroptosis
    DOI:  https://doi.org/10.3390/ijms251910832
  22. J Physiol. 2024 Oct 10.
    A simulation study on the role of mitochondria-sarcoplasmic reticulum Ca2+ interaction in cardiomyocyte energetics during exercise.
    Ayako Takeuchi, Satoshi Matsuoka.
      Previous studies demonstrated that the mitochondrial Ca2+ uniporter MCU and the Na+-Ca2+ exchanger NCLX exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca2+ pump SERCA, respectively, creating a mitochondria-SR Ca2+ interaction. However, the physiological relevance of the mitochondria-SR Ca2+ interaction has remained unsolved. Furthermore, although mitochondrial Ca2+ has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases, the contribution of the Ca2+-dependent regulatory mechanisms to cellular functions under physiological conditions has been controversial. In this study, we constructed a new integrated model of human ventricular myocyte with excitation-contraction-energetics coupling and investigated systematically the contribution of mitochondria-SR Ca2+ interaction, especially focusing on cardiac energetics during dynamic workload transitions in exercise. Simulation analyses revealed that the spatial coupling of mitochondria and SR, particularly via mitochondrial Ca2+ uniport activity-RyR, was the primary determinant of mitochondrial Ca2+ concentration, and that the Ca2+-dependent regulatory mechanism facilitated mitochondrial NADH recovery during exercise and contributed to the stability of NADH in the workload transition by about 40%, while oxygen consumption rate and cytoplasmic ATP level were not influenced. We concluded that the mitochondria-SR Ca2+ interaction, created via the uneven distribution of Ca2+ handling proteins, optimizes the contribution of the mitochondrial Ca2+-dependent regulatory mechanism to stabilizing NADH during exercise. KEY POINTS: The mitochondrial Ca2+ uniporter protein MCU and the Na+-Ca2+ exchanger protein NCLX are reported to exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca2+ pump SERCA, respectively, creating a mitochondria-SR Ca2+ interaction in cardiomyocytes. Mitochondrial Ca2+ (Ca2+ mit) has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases. Here we constructed an integrated model of a human ventricular myocyte with excitation-contraction-energetics coupling and investigated the role of the mitochondria-SR Ca2+ interaction in cardiac energetics during exercise. Simulation analyses revealed that the spatial coupling particularly via mitochondrial Ca2+ uniport activity-RyR is the primary determinant of Ca2+ mit concentration, and that the activation of NADH-producing dehydrogenases by Ca2+ mit contributes to NADH stability during exercise. The mitochondria-SR Ca2+ interaction optimizes the contribution of Ca2+ mit to the activation of NADH-producing dehydrogenases.
    Keywords:  energetics; exercise; heart; mathematical modelling; mitochondria; sarcoplasmic reticulum
    DOI:  https://doi.org/10.1113/JP286054
  23. Clin Nutr. 2024 Oct 02. pii: S0261-5614(24)00358-3. [Epub ahead of print]43(12): 17-25
    Low serum glycine strengthens the association between branched-chain amino acids and impaired insulin sensitivity assessed before and after weight loss in a population with pre-diabetes: The PREVIEW_NZ cohort.
    Jia Jiet Lim, Utpal K Prodhan, Marta P Silvestre, Amy Y Liu, Jessica McLay, Mikael Fogelholm, Anne Raben, Sally D Poppitt, David Cameron-Smith.
       AIM: Accumulation of circulating branched-chain amino acids (BCAA) is a hallmark feature of impaired insulin sensitivity. As intracellular BCAA catabolism is dependent on glycine availability, we hypothesised that the concurrent measurement of circulating glycine and BCAA may yield a stronger association with markers of insulin sensitivity than either BCAA or glycine alone. This study therefore examined the correlative relationships of BCAA, BCAA and glycine together, plus glycine alone on insulin sensitivity-related markers before and after an 8-week low energy diet (LED) intervention.
    METHODS: This is a secondary analysis of the PREVIEW (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World) Study New Zealand sub-cohort. Eligible participants with pre-diabetes at baseline who achieved ≥8 % body weight loss following an LED intervention were included, of which 167 paired (Week 0 and Week 8) blood samples were available for amino acid analysis. Glycemic and other data were retrieved from the PREVIEW consortium database. Repeated measures linear mixed models were used to test the association between amino acids and insulin sensitivity-related markers (HOMA2-IR, glucose, insulin, and C-peptide).
    RESULTS: Elevated BCAA was associated with impaired insulin sensitivity (p < 0.05), with strength of association (ηp2) almost doubled when glycine was added to the model. However, glycine in isolation was not associated with insulin sensitivity-related markers. The magnitude (β-estimates) of positive association between BCAA and HOMA2-IR, and inverse association between glycine and HOMA2-IR, increased when body weight was higher (Body weight∗BCAA, Body weight∗glycine, p < 0.05, both).
    CONCLUSION: Low serum glycine strengthened the association between BCAA and impaired insulin sensitivity. Given that glycine is necessary to facilitate intracellular BCAA catabolism, measurement of glycine is necessary to complement BCAA analysis to comprehensively understand the contribution of amino acid metabolism in insulin sensitivity.
    CLINICAL TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (NCT01777893).
    Keywords:  Branched-chain amino acid; Glycine; Insulin; Obesity; Pre-diabetes; Weight loss
    DOI:  https://doi.org/10.1016/j.clnu.2024.09.047
  24. Cell Rep. 2024 Oct 15. pii: S2211-1247(24)01216-6. [Epub ahead of print]43(10): 114865
    Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock.
    Jiameng Sun, Yiming Zhang, Joshua A Adams, Cassandra B Higgins, Shannon C Kelly, Hao Zhang, Kevin Y Cho, Ulysses G Johnson, Benjamin M Swarts, Shun-Ichi Wada, Gary J Patti, Leah P Shriver, Brian N Finck, Erik D Herzog, Brian J DeBosch.
      Organisms integrate circadian and metabolic signals to optimize substrate selection to survive starvation, yet precisely how this occurs is unclear. Here, we show that hepatocyte Period1 (Per1) is selectively induced during fasting, and mice lacking hepatocyte Per1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. Transcriptomic analyses show failed induction of the fasting hepatokine Fgf21 in Per1-deficient mice, and single-nucleus multiome sequencing defines a putative responding hepatocyte subpopulation that fails to induce the chromatin accessibility near the Fgf21 locus. In vivo isotopic tracing and indirect calorimetry demonstrate that hepatocyte Per1-deficient mice fail to transit from oxidation of glucose to fat, which is completely reversible by exogenous FGF21 or by inhibiting pyruvate dehydrogenase. Strikingly, disturbing other core circadian genes does not perturb Per1 induction during fasting. We thus describe Per1 as an important mechanism by which hepatocytes integrate internal circadian rhythm and external nutrition signals to facilitate proper fuel utilization.
    Keywords:  CP: Metabolism; circadian clock; fasting; glucose oxidation; liver metabolism; metabolite tracing; single-nucleus multiome sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2024.114865
  25. Clin Nutr. 2024 Sep 26. pii: S0261-5614(24)00345-5. [Epub ahead of print]43(11): 174-184
    Short-term intermittent fasting and energy restriction do not impair rates of muscle protein synthesis: A randomised, controlled dietary intervention.
    Imre W K Kouw, Evelyn B Parr, Michael J Wheeler, Bridget E Radford, Rebecca C Hall, Joan M Senden, Joy P B Goessens, Luc J C van Loon, John A Hawley.
       BACKGROUND: Intermittent fasting (IF) is an effective energy restricted dietary strategy to reduce body and fat mass and improve metabolic health in individuals with either an overweight or obese status. However, dietary energy restriction may impair muscle protein synthesis (MPS) resulting in a concomitant decline in lean body mass. Due to periods of prolonged fasting combined with irregular meal intake, we hypothesised that IF would reduce rates of MPS compared to an energy balanced diet with regular meal patterns.
    AIMS: We assessed the impact of a short-term, ten days, alternate day fasting or a continuous energy restricted diet to a control diet on integrated rates of skeletal MPS in middle-aged males with overweight or obesity.
    METHODS: Twenty-seven middle-aged males with overweight or obesity (age: 44.6 ± 5.4 y; BMI: 30.3 ± 2.6 kg/m2) consumed a three-day lead-in diet, followed by a ten-day controlled dietary intervention matched for protein intake, as alternate day fasting (ADF: 62.5 energy (En)%, days of 25 En% alternated with days of 100 En% food ingestion), continuous energy restriction (CER: 62.5 En%), or an energy balanced, control diet (CON: 100 En%). Deuterated water (D2O) methodology with saliva, blood, and skeletal muscle sampling were used to assess integrated rates of MPS over the ten-day intervention period. Secondary measures included fasting plasma glucose, insulin, and gastrointestinal hormone concentrations, continuous glucose monitoring, and assessment of body composition.
    RESULTS: There were no differences in daily rates of MPS between groups (ADF: 1.18 ± 0.13, CER: 1.13 ± 0.16, and CON: 1.18 ± 0.18 %/day, P > 0.05). The reductions in body mass were greater in ADF and CER compared to CON (P < 0.001). Lean and fat mass were decreased by a similar magnitude across groups (main time effect, P < 0.001; main group effect, P > 0.05). Fasting plasma leptin concentrations decreased in ADF and CER (P < 0.001), with no differences in fasting plasma glucose or insulin concentrations between groups.
    CONCLUSION: Short-term alternate day fasting does not lower rates of MPS compared to continuous energy restriction or an energy balanced, control diet with matched protein intake. The prolonged effects of IF and periods of irregular energy and protein intake patterns on muscle mass maintenance remain to be investigated. This trial was registered under Australian New Zealand Clinical Trial Registry (https://www.anzctr.org.au), identifier no. ACTRN12619000757112.
    Keywords:  Chrono-nutrition; Dietary protein; Energy restriction; Intermittent fasting; Muscle mass; Muscle protein synthesis
    DOI:  https://doi.org/10.1016/j.clnu.2024.09.034
  26. Front Pharmacol. 2024 ;15 1409625
    Inhibiting glycosphingolipids alleviates cardiac hypertrophy by reducing reactive oxygen species and restoring autophagic homeostasis.
    Chunxin Jiang, Menglei Tan, Lunmeng Lai, Yanping Wang, Zijun Chen, Qing Xie, Yunsen Li.
       Introduction: Cardiac hypertrophy is a compensatory stress response produced by a variety of factors, and pathologic hypertrophy can lead to irreversible, severe cardiac disease. Glycosphingolipids (GSLs) are vital constituents of cells, and changes in their content and composition are important factors causing mitochondrial dysfunction in diabetic cardiomyopathy; however, the relationship between GSLs expression and cardiac hypertrophy and specific mechanisms associated with it are not clear.
    Methods: Here, using male C57BL/6 mice, we performed aortic arch reduction surgery to establish an animal model of pressure overload cardiac hypertrophy. In addition, phenylephrine was used in vitro to induce H9c2 cells and neonatal rat left ventricular myocytes (NRVMs) to establish a cellular hypertrophy model.
    Results: Mass spectrometry revealed that the composition of GSLs was altered in pressure overload-induced hypertrophied mouse hearts and in stimulated hypertrophied cardiomyocyte cell lines. Specifically, in both cases, the proportion of endogenous lactosylceramide (LacCer) was significantly higher than in controls. Inhibition of GSL synthesis with Genz-123346 in NRVMs reduced cell hypertrophy, as well as fibrosis and apoptosis. By Western blotting, we detected decreased intracellular expression of Sirt3 and elevated phosphorylation of JNK after phenylephrine stimulation, but this was reversed in cells pretreated with Genz-123346. Additionally, increased protein expression of FoxO3a and Parkin, along with a decreased LC3-II/I protein ratio in phenylephrine-stimulated cells (compared with unstimulated cells), indicated that the mitochondrial autophagy process was disrupted; again, pretreatment with Genz-123346 reversed that.
    Discussion: Our results revealed that changes in GSLs in cardiomyocytes, especially an increase of LacCer, may be a factor causing cellular hypertrophy, which can be alleviated by inhibition of GSLs synthesis. A possible mechanism is that GSLs inhibition increases the expression of Sirt3 protein, scavenges intracellular reactive oxygen species, and restores mitochondrial autophagy homeostasis, thereby lessening cardiomyocyte hypertrophy. In all, these results provide a new perspective for developing drugs for cardiac hypertrophy.
    Keywords:  cardiac hypertrophy; glycosphingolipid; lactosylceramide; mitochondrial autophagy; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2024.1409625
  27. Int J Cardiol Heart Vasc. 2024 Oct;54 101485
    Epicardial adipose tissue and exercise intolerance in HFpEF.
    Michelle Lobeek, Thomas M Gorter, Michiel Rienstra.
      
    DOI:  https://doi.org/10.1016/j.ijcha.2024.101485
  28. Biochem Pharmacol. 2024 Oct 16. pii: S0006-2952(24)00571-9. [Epub ahead of print] 116571
    Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction.
    Sandra Moraña-Fernández, Xocas Vázquez-Abuín, Alana Aragón-Herrera, Laura Anido-Varela, Javier García-Seara, Óscar Otero-García, Diego Rodríguez-Penas, Manuel Campos-Toimil, Manuel Otero-Santiago, Alexandre Rodrigues, Alexandre Gonçalves, Juliana Pereira Morais, Inês N Alves, Cláudia Sousa-Mendes, Inês Falcão-Pires, José Ramón González-Juanatey, Sandra Feijóo-Bandín, Francisca Lago.
      The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.
    Keywords:  Diastolic dysfunction; Heart failure with preserved ejection fraction; Metabolome; Sacubitril/valsartan; ZSF1
    DOI:  https://doi.org/10.1016/j.bcp.2024.116571
  29. Int J Mol Sci. 2024 Sep 25. pii: 10302. [Epub ahead of print]25(19):
    Cross-Species Studies Reveal That Dysregulated Mitochondrial Gene Expression and Electron Transport Complex I Activity Are Crucial for Sarcopenia.
    Ji-Yoon Lee, Su-Kyung Shin, Ji-Won Han, Eun-Young Kwon, Heekyong R Bae.
      The significance of complex I of the electron transport chain (ETC) in the aging process is widely acknowledged; however, its specific impact on the development of sarcopenia in muscle remains poorly understood. This study elucidated the correlation between complex I inhibition and sarcopenia by conducting a comparative analysis of skeletal muscle gene expression in sarcopenia phenotypes from rats, mice, and humans. Our findings reveal a common mechanistic link across species, particularly highlighting the correlation between the suppression of complex I of ETC activity and dysregulated mitochondrial transcription and translation in sarcopenia phenotypes. Additionally, we observed macrophage dysfunction alongside abnormal metabolic processes within skeletal muscle tissues across all species, implicating their pathogenic role in the onset of sarcopenia. These discoveries underscore the importance of understanding the shared mechanisms associated with complex I of ETC in sarcopenia development. The identified correlations provide valuable insights into potential targets for therapeutic interventions aimed at mitigating the impact of sarcopenia, a condition with substantial implications for aging populations.
    Keywords:  aging; electron transport complex I; macrophage; mitochondria; muscle; sarcopenia; skeletal
    DOI:  https://doi.org/10.3390/ijms251910302
  30. PLoS One. 2024 ;19(10): e0311107
    Visualizing VDAC1 in live cells using a tetracysteine tag.
    Johannes Pilic, Furkan E Oflaz, Benjamin Gottschalk, Yusuf C Erdogan, Wolfgang F Graier, Roland Malli.
      The voltage-dependent anion channel 1 (VDAC1) is a crucial gatekeeper in the outer mitochondrial membrane, controlling metabolic and energy homeostasis. The available methodological approaches fell short of accurate visualization of VDAC1 in living cells. To permit precise VDAC1 imaging, we utilized the tetracysteine (TC)-tag and visualized VDAC1 dynamics in living cells. TC-tagged VDAC1 had a cluster-like distribution on mitochondria. The labeling of TC-tagged VDAC1 was validated with immunofluorescence. The majority of VDAC1-TC-clusters were localized at endoplasmic reticulum (ER)-mitochondria contact sites. Notably, VDAC1 colocalized with BCL-2 Antagonist/Killer (BAK)-clusters upon apoptotic stimulation. Using this new tool, we were able to observe VDAC1-TC at mitochondrial fission sites. These findings highlight the suitability of the TC-tag for live-cell imaging of VDAC1, shedding light on the roles of VDAC1 in cellular processes.
    DOI:  https://doi.org/10.1371/journal.pone.0311107
  31. Int J Mol Sci. 2024 Sep 24. pii: 10278. [Epub ahead of print]25(19):
    The Oldest of Old Male C57B/6J Mice Are Protected from Sarcopenic Obesity: The Possible Role of Skeletal Muscle Protein Kinase B Expression.
    Thomas H Reynolds, Noa Mills, Dakembay Hoyte, Katy Ehnstrom, Alex Arata.
      The impact of aging on body composition and glucose metabolism is not well established in C57BL/6J mice, despite being a common pre-clinical model for aging and metabolic research. The purpose of this study was to examine the effect of advancing age on body composition, in vivo glucose metabolism, and skeletal muscle AKT expression in young (Y: 4 months old, n = 7), old (O: 17-18 months old, n = 10), and very old (VO: 26-27 month old, n = 9) male C57BL/6J mice. Body composition analysis, assessed by nuclear magnetic resonance, demonstrated O mice had a significantly greater fat mass and body fat percentage when compared to Y and VO mice. Furthermore, VO mice had a significantly greater lean body mass than both O and Y mice. We also found that the VO mice had greater AKT protein levels in skeletal muscle compared to O mice, an observation that explains a portion of the increased lean body mass in VO mice. During glucose tolerance (GT) testing, blood glucose values were significantly lower in the VO mice when compared to the Y and O mice. No age-related differences were observed in insulin tolerance (IT). We also assessed the glucose response to AMPK activation by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). The change in blood glucose following AICAR administration was significantly reduced in VO mice compared to Y and AG mice. Our findings indicate that lean body mass and AKT2 protein expression in muscle are significantly increased in VO mice compared to O mice. The increase in AKT2 likely plays a role in the greater lean body mass observed in the oldest of old mice. Finally, despite the increased GT, VO mice appear to be resistant to AMPK-mediated glucose uptake.
    Keywords:  aging; body composition; glucose metabolism; protein kinase B; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms251910278
  32. J Biophotonics. 2024 Oct 17. e202400274
    Photobiomodulation Enhances the Effect of Strength Training on Insulin Resistance Regardless of Exercise Volume in Mice Fed a High-Fat Diet.
    Juliana Sales Rodrigues Costa, Gabriela Silva, Isabela Carvalho Guimarães, Luis Filipe Rocha Silva, Saulo Soares da Silva, João Paulo de Paula Almeida, Cândido Celso Coimbra, Nivaldo Antonio Parizotto, Fernando Gripp, Marco Fabrício Dias-Peixoto, Elizabethe Adriana Esteves, Fabiano Trigueiro Amorim, Cleber Ferraresi, Flavio de Castro Magalhaes.
      The aim was to investigate the effects of different volumes of strength training (ST) in association with photobiomodulation (PBMt) in mice fed a high-fat diet (HFD) on insulin resistance (IR). Male Swiss albino mice were fed HFD and performed high- or low-volume (one-third) ST (3 days/week), associated with PBMt (660 nm + 850 nm; ~42 J delivered) or not (lights off). ST improved IR, lowered visceral adiposity and circulating cytokines, and increased skeletal muscle hypertrophy and mitochondrial activity. The smaller volume of ST did not interfere with the improvement in IR, mitochondrial activity, or inflammatory profile, but exerted a smaller effect on visceral adiposity and skeletal muscle hypertrophy. Association with PBMt further improved IR, regardless of ST volume, although it did not affect adiposity, mitochondrial activity, and the inflammatory profile. Interestingly, PBMt positively affected quadriceps, but attenuated gluteus maximus hypertrophy. The association with PBMt induced greater improvement than ST alone.
    Keywords:  adiposity; obesity; phototherapy; resistance training; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1002/jbio.202400274
  33. Biochim Biophys Acta Proteins Proteom. 2024 Oct 10. pii: S1570-9639(24)00062-1. [Epub ahead of print] 141055
    Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response.
    Melissa A E van de Wal, Cenna Doornbos, Janne Bibbe, Judith R Homberg, Clara van Karnebeek, Martijn A Huynen, Jaap Keijer, Evert M van Schothorst, Peter A C 't Hoen, Mirian C H Janssen, Merel J W Adjobo-Hermans, Mariusz R Wieckowski, Werner J H Koopman.
      Paediatric Leigh syndrome (LS) is an early-onset and fatal neurodegenerative disorder lacking treatment options. LS is frequently caused by mutations in the NDUFS4 gene, encoding an accessory subunit of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system. Whole-body Ndufs4 knockout (KO) mice (WB-KO mice) are widely used to study isolated CI deficiency, LS pathology and interventions. These animals develop a brain-specific phenotype via an incompletely understood pathomechanism. Here we performed a quantitative analysis of the sub-brain proteome in six-weeks old WB-KO mice vs. wildtype mice. Brain regions comprised of a brain slice (BrSl), cerebellum (CB), cerebral cortex (CC), hippocampus (HC), inferior colliculus (IC), and superior colliculus (SC). Proteome analysis demonstrated similarities between CC/HC, and between IC/SC, whereas BrSl and CB differed from these two groups and each other. All brain regions displayed greatly reduced levels of two CI structural subunits (NDUFS4, NDUFA12) and an increased level of the CI assembly factor NDUFAF2. The level of CI-Q module subunits was significantly more reduced in IC/SC than in BrSl/CB/CC/HC, whereas other OXPHOS complex levels were not reduced. Gene ontology and pathway analysis demonstrated specific and common proteome changes between brain regions. Across brain regions, upregulation of cold-shock-associated proteins, mitochondrial fatty acid (FA) oxidation and synthesis (mtFAS) were the most prominent. FA-related pathways were predominantly upregulated in CB and HC. Based upon these results, we argue that stimulation of these pathways is futile and pro-pathological and discuss alternative strategies for therapeutic intervention in LS. SIGNIFICANCE: The Ndufs4 knockout mouse model is currently the most relevant and most widely used animal model to study the brain-linked pathophysiology of human Leigh Syndrome (LS) and intervention strategies. We demonstrate that the Ndufs4 knockout brain engages futile and pro-pathological responses. These responses explain both negative and positive outcomes of intervention studies in Leigh Syndrome mice and patients, thereby guiding novel intervention opportunities.
    Keywords:  Brain; Fatty acids; Leigh syndrome; Pathomechanism; Proteomics
    DOI:  https://doi.org/10.1016/j.bbapap.2024.141055
  34. J Agric Food Chem. 2024 Oct 16.
    Alpha Hydroxyl Acids from Mume Fructus and Schisandrae Chinensis Fructus Prevent Obesity by Inhibiting Intestinal Lipase in Diet-Induced Obese Mice.
    Ying Deng, Baojing Zhang, Jiayue Wang, Yan Wang, Dawei Li, Lei Feng, Yan Tian, Xiaochi Ma, Guobiao Liang, Chao Wang.
      Restriction of lipid uptake and absorption from the diet is regarded as an efficient strategy for the management of obesity, while lipase inhibition could successfully block the digestion of dietary lipids. Mume Fructus (MF) and Schisandrae Chinensis Fructus (SCF) were used as fruits, the biological effect of which on obesity desired more attention. Herein, the extracts of MF and SCF displayed significant efficacy in managing obesity in mice fed with a high-fat diet, via the inhibition of hydrolase activity of lipase in the digestive tract. Using the bioactivity guidance strategy, citric acid and malic acid were identified as the major lipase inhibitors from MF and SCF, respectively, which could prevent body weight gain, along with adipose tissue formation, and alleviate hyperlipidemia and hepatic steatosis in obese mice. Above all, MF and SCF could be used for the management of obesity via the lipase inhibition by citric acid and malic acid, displaying potential applications in healthy foods, nutritional supplements, and pharmaceutical materials.
    Keywords:  Mume Fructus; Schisandrae Chinensis Fructus; alpha hydroxyl acids; intestinal lipase; obesity
    DOI:  https://doi.org/10.1021/acs.jafc.4c05679
  35. Br J Pharmacol. 2024 Oct 14.
    miR-210 as a therapeutic target in diabetes-associated endothelial dysfunction.
    Aida Collado, Tong Jiao, Eftychia Kontidou, Lucas Rannier Ribeiro Antonino Carvalho, Ekaterina Chernogubova, Jiangning Yang, Germana Zaccagnini, Allan Zhao, John Tengbom, Xiaowei Zheng, Bence Rethi, Michael Alvarsson, Sergiu-Bogdan Catrina, Ali Mahdi, Mattias Carlström, Fabio Martelli, John Pernow, Zhichao Zhou.
       BACKGROUND AND PURPOSE: MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes.
    EXPERIMENTAL APPROACH: Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used.
    KEY RESULTS: miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells.
    CONCLUSION AND IMPLICATIONS: This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target.
    Keywords:  endothelial dysfunction; high glucose; miR‐210; oxidative stress; type 2 diabetes
    DOI:  https://doi.org/10.1111/bph.17329
  36. J Clin Endocrinol Metab. 2024 Oct 14. pii: dgae727. [Epub ahead of print]
    Impaired Suppression of Plasma Lipid Extraction and its Partitioning Away from Muscle by Insulin in Humans with Obesity.
    Christos S Katsanos, Lee Tran, Nyssa Hoffman, Lori R Roust, Eleanna De Filippis, Lawrence J Mandarino, Kailin Johnsson, Marek Belohlavek, Matthew R Buras.
       CONTEXT: Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown.
    OBJECTIVE: We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and non-esterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR).
    METHODS: The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat.
    RESULTS: Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous, but not ingested, origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects.
    CONCLUSIONS: Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.
    Keywords:  forearm; insulin resistance; muscle; obesity; stable isotopes; triglycerides
    DOI:  https://doi.org/10.1210/clinem/dgae727
  37. J Physiol Biochem. 2024 Oct 18.
    Normobaric hypoxia accelerates high-intensity intermittent training-induced mitochondrial biogenesis (PGC-1α)- and dynamics (OPA1)-related protein expressions in rat gastrocnemius muscle.
    Shohei Dobashi, Toshinori Yoshihara, Yuji Ogura, Hisashi Naito.
      High-intensity intermittent training (HIIT) in a normobaric hypoxic environment enhances exercise capacity, possibly by increasing the mitochondrial content in skeletal muscle; however, the molecular mechanisms underlying these adaptations are not well understood. Therefore, we investigated whether HIIT under normobaric hypoxia can enhance the expression of proteins involved in mitochondrial biogenesis and dynamics in rat gastrocnemius muscle. Five-week-old male Wistar rats (n = 24) were randomly assigned to the following four groups: (1) sedentary under normoxia (20.9% O2) (NS), (2) training under normoxia (NT), (3) sedentary under normobaric hypoxia (14.5% O2) (HS), and (4) training under normobaric hypoxia (HT). The training groups in both conditions were engaged in HIIT on a treadmill five to six days per week for nine weeks. From the fourth week of the training period, the group assigned to hypoxic conditions was exposed to normobaric hypoxia. Forty-eight hours after completing the final training session, gastrocnemius muscles were surgically removed, and mitochondrial enzyme activity and mitochondrial biogenesis and dynamics regulatory protein levels were determined. Citrate synthase (CS) activity and mitochondrial oxygen phosphorylation (OXPHOS) subunits in the gastrocnemius muscle in the HT significantly exceeded those in the other three groups. Moreover, the levels of a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and a mitochondrial fusion-related protein, optic atrophy 1 (OPA1), were significantly increased by HIIT under normobaric hypoxia. Our data indicates that HIIT and normobaric hypoxia increase the expression of mitochondrial biogenesis- and dynamics-related proteins in skeletal muscles.
    Keywords:  Autophagy; Hind limb muscle; Mitochondrial fusion and fission; Mitochondrial synthesis; Moderate hypoxia; Treadmill running
    DOI:  https://doi.org/10.1007/s13105-024-01052-9
  38. Med Sci Sports Exerc. 2024 Oct 15.
    Modulators of Energy Expenditure Accuracy in Adults with Overweight or Obesity: E-MECHANIC Secondary Analyses.
    Rachel Matthews, Christoph Höchsmann, Melissa L Erickson, James L Dorling, Guillaume Spielmann, Neil M Johannsen, Timothy S Church, Corby K Martin.
       PURPOSE: American College of Sports Medicine (ACSM) metabolic equations are used to estimate energy expenditure (EE) of physical activity and prescribe aerobic exercise to meet EE requirements. Limited evidence supports their accuracy in sedentary adults with overweight or obesity during controlled exercise interventions. The purpose of this study was to compare EE estimated by the ACSM walking equation versus EE measured by indirect calorimetry during a 24-week aerobic exercise intervention, and identify potential modulators for their accuracy.
    METHODS: Data from the exercising groups (8 or 20 kcal·kg body weight-1·week-1) of the E-MECHANIC study were utilized in this ancillary analysis (N = 103). Every 2 weeks for the initial 8 weeks and monthly thereafter, EE was measured via indirect calorimetry during absolute (2 mph, 0% grade) and relative (65-85% VO2peak) workload exercise. Resting metabolic rate, VO2peak, and body composition were assessed at baseline and follow-up. An EE offset factor (EOF) was calculated to express measured EE as a percentage of the estimated EE at each workload (EOF < 100% represents an overestimation of ACSM estimated EE).
    RESULTS: The accuracy of the equation decreased with increasing exercise workload (0.44%, 9.2%, and 20.3% overestimation at absolute, relative, and maximal workloads, respectively, at baseline) and overestimation of EE was greater after the exercise intervention. Furthermore, race, sex, age, fat mass, and VO2peak were identified as modulators for equation accuracy. Greater overestimation of EE was observed in Black compared to white females, particularly at lower exercise workloads.
    CONCLUSIONS: These findings support future efforts to improve the accuracy of metabolic equations, especially in diverse populations. Researchers should account for exercise efficiency adaptations when using metabolic equations to prescribe exercise precisely.
    DOI:  https://doi.org/10.1249/MSS.0000000000003583
  39. NPJ Metab Health Dis. 2024 ;pii: 4. [Epub ahead of print]2
    Limitations in metabolic plasticity after traumatic injury are only moderately exacerbated by physical activity restriction.
    Angela S Bruzina, Christiana J Raymond-Pope, Kevin J Murray, Thomas J Lillquist, Katelyn M Castelli, Shefali R Bijwadia, Jarrod A Call, Sarah M Greising.
      Following traumatic musculoskeletal injuries, prolonged bedrest and loss of physical activity may limit muscle plasticity and drive metabolic dysfunction. One specific injury, volumetric muscle loss (VML), results in frank loss of muscle and is characterized by whole-body and cellular metabolic dysfunction. However, how VML and restricted physical activity limit plasticity of the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle remains unclear. Adult mice were randomized to posterior hindlimb compartment VML or were age-matched injury naïve controls, then randomized to standard or restricted activity cages for 8-wks. Activity restriction in naïve mice resulted in ~5% greater respiratory exchange ratio (RER); combined with VML, carbohydrate oxidation was ~23% greater than VML alone, but lipid oxidation was largely unchanged. Activity restriction combined with VML increased whole-body carbohydrate usage. Together there was a greater pACC:ACC ratio in the muscle remaining, which may contribute to decreased fatty acid synthesis. Further, β-HAD activity normalized to mitochondrial content was decreased following VML, suggesting a diminished capacity to oxidize fatty acids. The muscle metabolome was not altered by the restriction of physical activity. The combination of VML and activity restriction resulted in similar (~91%) up- and down-regulated metabolites and/or ratios, suggesting that VML injury alone is regulating changes in the metabolome. Data supports possible VML-induced alterations in fatty acid metabolism are exacerbated by activity restriction. Collectively, this work adds to the sequala of VML injury, exhausting the ability of the muscle remaining to oxidize fatty acids resulting in a possible accumulation of triglycerides.
    Keywords:  Metabolic flexibility; fat metabolism; metabolomics; orthopaedic trauma; skeletal muscle injury; volumetric muscle loss
    DOI:  https://doi.org/10.1038/s44324-024-00006-5
  40. Eur J Pharmacol. 2024 Oct 10. pii: S0014-2999(24)00745-3. [Epub ahead of print]984 177055
    Pharmacological inhibition reveals participation of the endocytic compartment in positive feedback IL-6 secretion in human skeletal myotubes.
    Blanca Calle-Ciborro, Francisco J Santos, Teresa Espin-Jaime, Ana Gomez-Martin, Pedro J Camello, Cristina Camello-Almaraz.
      IL-6 is an important cytokine involved in metabolic, immunological, and cell-fate responses. It is released upon stimulation by skeletal muscle cells through partially characterized mechanisms. In some cell types, IL-6 has been reported to activate a positive feedback loop involving endocytic vesicles, but evidence is mostly based on transcription and signal transduction mechanisms and is very scarce in muscle cells. Our aim was to directly demonstrate the presence of positive feedback in the ATP-induced release of IL-6 into the supernatant of human skeletal muscle cultures. The total release (production) of IL-6 was reduced for higher volumes of supernatant, when the secreted IL-6 molecules are more diluted, and enhanced when the supernatant volume was lower. In addition, secretion was impaired both by tocilizumab, a blocker of human IL-6 receptors, and by the soluble form of the receptor. The secretion in response to ATP was also inhibited by treatment with the endocytosis inhibitor dynasore, and by disruption of the acidic gradient of the endocytic compartment using different methods (chloroquine, NH4Cl or monensin). IL-6 secretion was also impaired by NED-19, a specific inhibitor of the two pore channels receptor mediating Ca2+ release from the endolysosomal compartment. IL-6 and ATP increased IL-6 mRNA levels, an effect blocked by tocilizumab. Altogether, our results demonstrate that ATP-secreted IL-6 activates a positive loop based on IL-6 receptors, endocytosis, two pore channels and IL-6 transcription. Given the importance of muscle IL-6 as a systemic regulator and as an inflammatory mediator, our study can help to understand muscle pathophysiology.
    Keywords:  ATP; Endocytosis; IL-6; IL-6 receptor; Skeletal muscle; Two pore channels
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177055
  41. Nucleus. 2024 Dec;15(1): 2413501
    Apoptosis-induced translocation of nesprin-2 from the nuclear envelope to mitochondria is associated with mitochondrial dysfunction.
    Hila Zohar, Liora Lindenboim, Oren Gozlan, Gregg G Gundersen, Howard J Worman, Reuven Stein.
      Accumulating evidence suggests that the nuclear envelope (NE) is not just a target, but also a mediator of apoptosis. We showed recently that the NE protein nesprin-2 has pro-apoptotic activity, which involves its subcellular redistribution and Bcl-2 proteins. Here we further characterize the pro-apoptotic activity of nesprin-2 focusing on its redistribution. We assessed the redistribution kinetics of endogenous nesprin-2 tagged with GFP relative to apoptosis-associated mitochondrial dysfunction. The results show apoptosis-induced GFP-nesprin-2G redistribution occurred by two different modes - complete and partial, both lead to appearance of nesprin-2G near the mitochondria. Moreover, GFP-nesprin-2 redistribution is associated with reduction in mitochondrial membrane potential and mitochondrial outer membrane permeabilization and precedes the appearance of morphological features of apoptosis. Our results show that nesprin-2G redistribution and translocation near mitochondria is an early apoptotic effect associated with mitochondrial dysfunction, which may be responsible for the pro-apoptotic function of nesprin-2.
    Keywords:  Apoptosis; LINC complex; mitochondria; nesprin-2; nuclear envelope; nucleus
    DOI:  https://doi.org/10.1080/19491034.2024.2413501
  42. Int J Mol Sci. 2024 Oct 01. pii: 10577. [Epub ahead of print]25(19):
    The Novel Anticancer Aryl-Ureido Fatty Acid CTU Increases Reactive Oxygen Species Production That Impairs Mitochondrial Fusion Mechanisms and Promotes MDA-MB-231 Cell Death.
    Stanton Tam, Balasubrahmanyam Umashankar, Md Khalilur Rahman, Hassan Choucair, Tristan Rawling, Michael Murray.
      Cancer cell mitochondria are functionally different from those in normal cells and could be targeted to develop novel anticancer agents. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of targeted agents that enhance the production of reactive oxygen species (ROS) that disrupt the outer mitochondrial membrane (OMM) and kill cancer cells. However, the mechanism by which CTU disrupts the inner mitochondrial membrane (IMM) and activates apoptosis is not clear. Here, we show that CTU-mediated ROS selectively dysregulated the OMA1/OPA1 fusion regulatory system located in the IMM. The essential role of ROS was confirmed in experiments with the lipid peroxyl scavenger α-tocopherol, which prevented the dysregulation of OMA1/OPA1 and CTU-mediated MDA-MB-231 cell killing. The disruption of OMA1/OPA1 and IMM fusion by CTU-mediated ROS accounted for the release of cytochrome c from the mitochondria and the activation of apoptosis. Taken together, these findings demonstrate that CTU depolarises the mitochondrial membrane, activates ROS production, and disrupts both the IMM and OMM, which releases cytochrome c and activates apoptosis. Mitochondrial-targeting agents like CTU offer a novel approach to the development of new therapeutics with anticancer activity.
    Keywords:  anticancer agent; aryl-ureido fatty acids; mitochondrial fission and fusion; mitochondrial membrane; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms251910577
  43. Aging Cell. 2024 Oct 18. e14369
    Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes.
    Steven K Malin, Daniel J Battillo, Michal S Beeri, Maja Mustapic, Francheska Delgado-Peraza, Dimitrios Kapogiannis.
      Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short-term exercise would raise neuronal insulin signaling and pro-BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty-one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m2) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work-matched continuous (n = 13, 70% HRpeak) or interval (n = 8, 90% HRpeak and 50% HRpeak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time-points of the OGTT, and levels of insulin signaling proteins (i.e., p-IRS-1, total-/p-Akt, pERK1/2, pJNK1/2, and pp38) and pro-BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60-0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO2peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (-0.4 ± 0.9 kg, p = 0.04) and whole-body glucose tAUC120min (p = 0.02). Training lowered 0-min pro-BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, p = 0.04) and increased OGTT-stimulated tAkt (-51.8 ± 147.2 vs. 95 ± 204.5 a.u., p = 0.01), which was paralleled by reduced pAkt/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro-BNDF among adults with prediabetes, thereby potentially lowering ADRD risk.
    Keywords:  aging; glucose tolerance; insulin sensitivity; obesity; physical activity; type 2 diabetes
    DOI:  https://doi.org/10.1111/acel.14369
  44. Eur J Med Chem. 2024 Oct 05. pii: S0223-5234(24)00820-1. [Epub ahead of print]280 116939
    Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione's in fructose induced insulin resistant rats.
    Shriram D Ranade, Shankar G Alegaon, Nayeem A Khatib, Shankar Gharge, Rohini S Kavalapure, B R Prashantha Kumar.
      In our pursuit of discovering new antidiabetic agents to manage type 2 diabetes mellitus (T2DM), our approach aimed to identify the bioactive feature/pharmacophore responsible for PPAR-γ expression, as it is accountable for the glucose homeostasis and lipid metabolism. This was achieved by pharmacophore model generation, screening of rationally designed newer thiazolidinedione's library, identifying synthesizing and characterizing the top ten molecules (5a-5j) for their (Invitro & invivo) antidiabetic activity. Preliminary screening of all the ligands by Invitro glucose uptake assay in L6 myotubes (skeletal muscle cell line of rats) revealed compound 5b and 5f stimulated the glucose uptake with 79.29 ± 1.02 % and 74.58 ± 1.02 % respectively compared to pioglitazone with 82.36 ± 0.98 %. This was validated by PPAR-γ TF expression assay, which highlighted a dose dependent increase in transactivation of PPAR-γ. These compounds 5b and 5f were evaluated in fructose induced insulin resistance rat model. Where the treatment with 5b and 5f markedly increased the exogenous clearance of glucose and exogenous insulin via OGTT and ITT respectively, also improved the glucose utilization by significantly increasing content of glycogen and uptake of glucose in rat hemidiaphragm and reversed insulin resistance. Likewise a significant decreased in the VLDL and triglyceride levels was seen in 5b and 5f treated groups compared to insulin resistant (IR) group. It improved glycogenesis by catabolism of glucose and maintained glycaemic control. Similarly it had marked action on enzymatic oxidative biomarkers. Compound 5b displayed better, improved T1/2 (half-life) of 4.21 h and Kel (elimination constant) of 0.381 was noticed in comparison to compound 5f indicating the pharmacokinetic profile. Insilico studies like DFT calculations refined the geometry of 5b and 5f ligands, docking and molecular simulation provided the insights in binding affinity, dynamic behaviour and stability of ligands in PPAR-γ ligand binding domain. MM/GBSA provided the energetics of 5b and 5f in binding pocket. Finally network pharmacology identified ADIPOQ (adiponectin), NR1C3 (PPAR-γ), SLC2A4 (GLUT4), and LEP (leptin) proteins associate with compound 5b and 5f and enriched in Adipocytokine pathway, and PPAR-γ signaling pathway.
    Keywords:  MD simulations; Network pharmacology; Thiazolidinedione's; Type 2 diabetes mellitus; insulin resistance
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116939
  45. Int J Mol Sci. 2024 Sep 27. pii: 10402. [Epub ahead of print]25(19):
    Profiling Reduced Expression of Contractile and Mitochondrial mRNAs in the Human Sinoatrial Node vs. Right Atrium and Predicting Their Suppressed Expression by Transcription Factors and/or microRNAs.
    Weixuan Chen, Abimbola J Aminu, Zeyuan Yin, Irem Karaesmen, Andrew J Atkinson, Marcin Kuniewicz, Mateusz Holda, Jerzy Walocha, Filip Perde, Peter Molenaar, Halina Dobrzynski.
      (1) Background: The sinus node (SN) is the main pacemaker of the heart. It is characterized by pacemaker cells that lack mitochondria and contractile elements. We investigated the possibility that transcription factors (TFs) and microRNAs (miRs) present in the SN can regulate gene expression that affects SN morphology and function. (2) Methods: From human next-generation sequencing data, a list of mRNAs that are expressed at lower levels in the SN compared with the right atrium (RA) was compiled. The mRNAs were then classified into contractile, mitochondrial or glycogen mRNAs using bioinformatic software, RStudio and Ingenuity Pathway Analysis. The mRNAs were combined with TFs and miRs to predict their interactions. (3) Results: From a compilation of the 1357 mRNAs, 280 contractile mRNAs and 198 mitochondrial mRNAs were identified to be expressed at lower levels in the SN compared with RA. TFs and miRs were shown to interact with contractile and mitochondrial function-related mRNAs. (4) Conclusions: In human SN, TFs (MYCN, SOX2, NUPR1 and PRDM16) mainly regulate mitochondrial mRNAs (COX5A, SLC25A11 and NDUFA8), while miRs (miR-153-3p, miR-654-5p, miR-10a-5p and miR-215-5p) mainly regulate contractile mRNAs (RYR2, CAMK2A and PRKAR1A). TF and miR-mRNA interactions provide a further understanding of the complex molecular makeup of the SN and potential therapeutic targets for cardiovascular treatments.
    Keywords:  Ingenuity Pathway Analysis; contractile function; glycogen metabolism; human right atrium; human sinus node/sinoatrial node; miRNA; mitochondrial function; transcription factor
    DOI:  https://doi.org/10.3390/ijms251910402
  46. Cell. 2024 Oct 03. pii: S0092-8674(24)01087-0. [Epub ahead of print]
    Structural basis of respiratory complex adaptation to cold temperatures.
    Young-Cheul Shin, Pedro Latorre-Muro, Amina Djurabekova, Oleksii Zdorevskyi, Christopher F Bennett, Nils Burger, Kangkang Song, Chen Xu, Joao A Paulo, Steven P Gygi, Vivek Sharma, Maofu Liao, Pere Puigserver.
      In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) supercomplex was identified with a ∼25° rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.
    Keywords:  CIII(2) rotation; brown adipose tissue; cellular adaptation; electron transport chain; membrane lipid remodeling; respiratory complexes
    DOI:  https://doi.org/10.1016/j.cell.2024.09.029
  47. EMBO J. 2024 Oct 17.
    An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.
    Nan Zhao, Antonio Michelucci, Laura Pietrangelo, Sundeep Malik, Linda Groom, Jennifer Leigh, Thomas N O'Connor, Takahiro Takano, Paul D Kingsley, James Palis, Simona Boncompagni, Feliciano Protasi, Robert T Dirksen.
      Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.
    Keywords:  Calcium Signaling; Mitochondria; Muscle Disease; ORAI1; Proteomics
    DOI:  https://doi.org/10.1038/s44318-024-00273-4
  48. Hypertens Res. 2024 Oct 14.
    Myosteatosis and sarcopenia are linked to autonomous cortisol secretion in patients with aldosterone-producing adenomas.
    TAIPAI Study Group
      Patients with adrenal aldosterone-producing adenomas (APA) face elevated cardiovascular risks, especially when cortisol is co-secreted, yet the impact on muscle health remains unclear. Myosteatosis, characterized by fatty infiltration into muscles, is linked to cardiometabolic diseases and decreased survival. We aimed to investigate the association between autonomous cortisol secretion (ACS) in APA and muscle quantity and quality. In this study, we analyzed data from 228 APA patients undergoing laparoscopic adrenalectomy between 2009 and 2024, assessing muscle composition via computed tomography. Intermuscular adipose tissue (IMAT), skeletal muscle area and density, visceral and subcutaneous adipose tissue area at L3 were measured. Comparisons were made between ACS and non-ACS groups. We found that among 228 patients, 76 (33.3%) had ACS. Those with ACS exhibited significantly higher IMAT area (P = 0.042) and lower skeletal muscle area (P = 0.002) and density (P < 0.001). Multivariable regression confirmed ACS positively associated with IMAT area and negatively associated with skeletal muscle area and density. At 1-year follow-up, ACS patients (n = 15) experienced decreased IMAT area (P = 0.001) and increased skeletal muscle area (P = 0.031) post-adrenalectomy, while those without ACS (n = 29) showed no IMAT change but increased visceral (P < 0.001) and subcutaneous (P = 0.008) adipose tissue area. In summary, myosteatosis and sarcopenia are linked to ACS in APA patients, and these parameters improve following adrenalectomy.
    Keywords:  Autonomous cortisol secretion; Body composition; Glucocorticoids; Hyperaldosteronism; Myosteatosis; Sarcopenia
    DOI:  https://doi.org/10.1038/s41440-024-01933-y
  49. Biochim Biophys Acta Mol Basis Dis. 2024 Oct 15. pii: S0925-4439(24)00536-2. [Epub ahead of print]1871(1): 167542
    PFKP inhibition protects against pathological cardiac hypertrophy by regulating protein synthesis.
    Xiao-Yu Wu, Shi Peng, Xin-Tao Li, Song-Wen Chen, Yong Wei, Yu-Tong Ye, Chang-Zuan Zhou, Zi-Kan Zhong, Long-Zhe Gao, Chen-Yang Jin, De-Ping Kong, Shao-Wen Liu, Gen-Qing Zhou.
      Metabolic reprogramming precedes most alterations during pathological cardiac hypertrophy and heart failure (HF). Recent studies have revealed that Phosphofructokinase, platelet (PFKP) has a wealth of metabolic and non-metabolic functions. In this study, we explored the role of PFKP in cardiac hypertrophic growth and HF. The expression level of PFKP was elevated both in pathological cardiac remodeling mouse model challenged by transverse aortic constriction (TAC) surgery and in the neonatal rat cardiomyocytes (NRCMs) stimulated by phenylephrine (PE). In global PFKP knockout (PFKP-KO) mice, cardiac hypertrophy was ameliorated under TAC surgery, while overexpression of PFKP by intravenous injection of adeno-associated virus 9 (AAV9) under the cardiac troponin T (cTnT) promoter worsened myocardial hypertrophy and fibrosis. In NRCMs, small interfering RNA (SiRNA) knockdown or adenovirus (Adv) overexpression of PFKP was employed and the intervention of PFKP showed a similar phenotype. Mechanistically, immunoprecipitation combined with liquid chromatography-tandem mass spectrometry (IP-MS/MS) analysis was used to identify the interacting proteins of PFKP. Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) was identified as the downstream target of PFKP. In the PE-stimulated NRCM hypertrophy model and mouse TAC model, knocking down EIF2S2 after PFKP overexpression reduced the synthesis of new proteins and alleviated the hypertrophy phenotype. Our findings illuminate that PFKP participates in pathological cardiac hypertrophy partly by regulating protein synthesis through EIF2S2, which provides a new clue for the involvement of metabolic intermediates in signal transduction.
    Keywords:  EIF2S2; Hypertrophy; Myocyte, cardiac; PFKP; Protein synthesis
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167542
  50. Methods Mol Biol. 2025 ;2861 155-164
    Analyzing Mitochondrial Calcium Influx in Isolated Mitochondria.
    Nasab Ghazal, Jennifer Q Kwong.
      Mitochondria play a crucial role in Ca2+ signaling and homeostasis and can contribute to shaping the cytosolic Ca2+ landscape as well as regulate a variety of pathways including energy production and cell death. Dysregulation of mitochondrial Ca2+ homeostasis promotes pathologies including neurodegenerative diseases, cardiovascular disorders, and metabolic syndromes. The significance of mitochondria to Ca2+ signaling and regulation underscores the value of methods to assess mitochondrial Ca2+ import. Here we present a plate reader-based method using the Ca2+-sensitive fluorescent probe calcium green-5 N to measure mitochondrial Ca2+ import in isolated cardiac mitochondria. This technique can be expanded to measure Ca2+ uptake in mitochondria isolated from other tissue types and from cultured cells.
    Keywords:  Calcium; Heart; Mitochondria; Mitochondrial permeability transition pore; Signaling; Uniporter
    DOI:  https://doi.org/10.1007/978-1-0716-4164-4_12
  51. Int J Mol Sci. 2024 Oct 08. pii: 10792. [Epub ahead of print]25(19):
    The Downregulation of the Liver Lipid Metabolism Induced by Hypothyroidism in Male Mice: Metabolic Flexibility Favors Compensatory Mechanisms in White Adipose Tissue.
    Lamis Chamas, Isabelle Seugnet, Odessa Tanvé, Valérie Enderlin, Marie-Stéphanie Clerget-Froidevaux.
      In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (THs), through their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, which leads to a reduction in energy expenditure as well as in lipid and glucose metabolism. The objective of this study was to evaluate whether the metabolic deregulations induced by hypothyroidism could be avoided through regulatory mechanisms involved in metabolic flexibility. To this end, the response to induced hypothyroidism was compared in males from two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and C57BL/6J mice, which are prone to DIO. The results show that propylthiouracil (PTU)-induced hypothyroidism led to metabolic deregulations, particularly a reduction in hepatic lipid synthesis in both strains. Furthermore, in contrast to the C57BL/6J mice, the WSB/EiJ mice were resistant to the metabolic dysregulations induced by hypothyroidism, mainly through enhanced lipid metabolism in their adipose tissue. Indeed, WSB/EiJ mice compensated for the decrease in hepatic lipid synthesis by mobilizing lipid reserves from white adipose tissue. Gene expression analysis revealed that hypothyroidism stimulated the hypothalamic orexigenic circuit in both strains, but there was unchanged melanocortin 4 receptor (Mc4r) and leptin receptor (LepR) expression in the hypothyroid WSB/EiJ mice strain, which reflects their adaptability to maintain their body weight, in contrast to C57BL/6J mice. Thus, this study showed that WSB/EiJ male mice displayed a resistance to the metabolic dysregulations induced by hypothyroidism through compensatory mechanisms. This highlights the importance of metabolic flexibility in the ability to adapt to disturbed circulating TH levels.
    Keywords:  PTU (propylthiouracil); hypothyroidism; lipogenesis; liver; metabolic flexibility; white adipose tissue
    DOI:  https://doi.org/10.3390/ijms251910792
  52. Int J Mol Sci. 2024 Sep 25. pii: 10297. [Epub ahead of print]25(19):
    GQ262 Attenuates Pathological Cardiac Remodeling by Downregulating the Akt/mTOR Signaling Pathway.
    Haoyue Ma, Yang Ge, Chang Di, Xin Wang, Boyang Qin, Anhui Wang, Weipeng Hu, Zirui Lai, Xiaofeng Xiong, Rong Qi.
      Cardiac remodeling, a critical process that can lead to heart failure, is primarily characterized by cardiac hypertrophy. Studies have shown that transgenic mice with Gαq receptor blockade exhibit reduced hypertrophy under induced pressure overload. GQ262, a novel Gαq/11 inhibitor, has demonstrated good biocompatibility and specific inhibitory effects on Gαq/11 compared to other inhibitors. However, its role in cardiac remodeling remains unclear. This study aims to explore the anti-cardiac remodeling effects and mechanisms of GQ262 both in vitro and in vivo, providing data and theoretical support for its potential use in treating cardiac remodeling diseases. Cardiac hypertrophy was induced in mice via transverse aortic constriction (TAC) for 4 weeks and in H9C2 cells through phenylephrine (PE) induction, confirmed with WGA and H&E staining. We found that GQ262 improved cardiac function, inhibited the protein and mRNA expression of hypertrophy markers, and reduced the levels of apoptosis and fibrosis. Furthermore, GQ262 inhibited the Akt/mTOR signaling pathway activation induced by TAC or PE, with its therapeutic effects disappearing upon the addition of the Akt inhibitor ARQ092. These findings reveal that GQ262 inhibits cardiomyocyte hypertrophy and apoptosis through the Akt/mTOR signaling pathway, thereby reducing fibrosis levels and mitigating cardiac remodeling.
    Keywords:  Akt/mTOR; GQ262; Gαq/11; apoptosis; cardiac hypertrophy; fibrosis
    DOI:  https://doi.org/10.3390/ijms251910297
  53. Signal Transduct Target Ther. 2024 Oct 16. 9(1): 273
    Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα-TRAF3-TAK1-MAPK axis.
    Lin Xie, Fei Xue, Cheng Cheng, Wenhai Sui, Jie Zhang, Linlin Meng, Yue Lu, Wenjing Xiong, Peili Bu, Feng Xu, Xiao Yu, Bo Xi, Lin Zhong, Jianmin Yang, Cheng Zhang, Yun Zhang.
      The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.
    DOI:  https://doi.org/10.1038/s41392-024-01977-z
  54. J Diabetes Investig. 2024 Oct 16.
    Improvement of heart rate variability after metabolic bariatric surgery in Korean subjects with obesity.
    Han Na Jang, Young Suk Park, Joon Ho Moon, Sung Hee Choi, Hak Chul Jang, Tae Jung Oh.
       INTRODUCTION: Cardiovascular autonomic neuropathy (CAN) is a chronic complication of diabetes. As obesity is a major risk factor for CAN, we hypothesized that metabolic bariatric surgery (MBS) could improve CAN indices in Korean patients with obesity.
    MATERIALS AND METHODS: Patients who underwent bariatric surgery between February 2020 and June 2022 were prospectively recruited. CAN was conducted once before surgery and again after surgery, using the Ewing method and heart rate variability (HRV) analysis (standard deviation of the NN interval [SDNN], root mean square of successive RR interval difference [RMSSD], and spectral analysis).
    RESULTS: A total of 47 patients were included. The mean age was 39.8 ± 8.7 years, 15 (31.9%) were male, and 26 (55.3%) had diabetes. Resting HR before surgery was 81.0 ± 12.3 bpm, which decreased significantly to 68.0 ± 9.3 bpm after surgery (P < 0.001). Changes in HR and BP according to the Valsalva maneuver, postural changes, and handgrip were not significantly different before and after surgery. However, SDNN significantly increased from 25.2 [15.1, 33.5] to 38.0 [25.4, 45.0] ms (P < 0.001), and RMSSD also significantly increased from 17.0 [9.2, 31.8] to 28.2 [15.3, 45.6] ms (P = 0.001). Both low-frequency power (LF) and high-frequency power (HF) increased significantly, and the LF/HF ratio significantly decreased from 2.1 ± 1.6 to 1.3 ± 1.3 (P = 0.010). Loss of weight, fat mass, and lean body mass were independently associated with improving the HRV variables.
    CONCLUSIONS: MBS improved HRV variables, and these changes were mainly associated with postoperative weight loss.
    Keywords:  Cardiovascular autonomic neuropathy; Heart rate variability; Metabolic bariatric surgery
    DOI:  https://doi.org/10.1111/jdi.14332
  55. Eur Heart J. 2024 Oct 16. pii: ehae676. [Epub ahead of print]
    The heart is a muscle: on-call fitness guide for the busy cardiovascular surgeon and interventionalist.
    Samantha Colon, Adham Ahmed, Irbaz Hameed.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehae676
  56. J Biol Chem. 2024 Oct 16. pii: S0021-9258(24)02401-3. [Epub ahead of print] 107899
    Suppressed ORAI1-STIM1-dependent Ca2+ entry by protein kinase C isoforms regulating platelet procoagulant activity.
    Jinmi Zou, Pengyu Zhang, Fiorella A Solari, Claudia Schönichen, Isabella Provenzale, Nadine J A Mattheij, Marijke J E Kuijpers, Julia S Rauch, Frauke Swieringa, Albert Sickmann, Barbara Zieger, Kerstin Jurk, Johan W M Heemskerk.
      Agonist-induced rises in cytosolic Ca2+ control most platelet responses in thrombosis and hemostasis. In human platelets we earlier demonstrated that the ORAI1-STIM1 pathway is a major component of extracellular Ca2+ entry, in particular when induced via the ITAM-linked collagen receptor, glycoprotein VI (GPVI). In the present paper, using functionally defective platelets from patients with a loss-of-function mutation in ORAI1 or STIM1, we show that Ca2+ entry induced by the endoplasmic reticulum ATPase inhibitor, thapsigargin, fully relies on this pathway. We demonstrate that both the GPVI-induced and thapsigargin-induced Ca2+ entry is strongly suppressed by protein kinase C (PKC) activation, while leaving intracellular Ca2+ mobilization unchanged. Comparing effects of a PKC inhibitory panel pointed to redundant roles of beta and theta PKC isoforms in Ca2+-entry suppression. In contrast, tyrosine kinases positively regulated GPVI-induced Ca2+ entry and mobilization. Label-free and stable isotope phosphoproteome analysis of GPVI-stimulated platelets suggested a regulatory role of bridging integrator-2 (BIN2), known as important mediator of the ORAI1-STIM1 pathway in mouse platelets. Identified were 25-45 regulated phospho- sites in BIN2 and 16-18 in STIM1. Five of these were characterized as direct substrates of the expressed PKC isoforms alpha, beta delta and theta. Functional platelet testing indicated that the downregulation of Ca2+ entry by PKC resulted in suppressed phosphatidylserine exposure and plasmatic thrombin generation. Conclusively, our results indicate that in platelets multiple PKC isoforms constrain the store-regulated Ca2+ entry via ORAI1-BIN2-STIM1, and hence downregulate platelet-dependent coagulation.
    Keywords:  calcium channel; hemostasis; phosphoproteomics; platelet; protein kinase C
    DOI:  https://doi.org/10.1016/j.jbc.2024.107899
  57. Diabetes. 2024 Oct 17. pii: db240451. [Epub ahead of print]
    Multi-Omics Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.
    Daniel B Rosoff, Josephin Wagner, Jeesun Jung, Pal Pacher, Constantinos Christodoulides, George Davey Smith, David Ray, Falk W Lohoff.
      The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.
    DOI:  https://doi.org/10.2337/db24-0451
  58. Heliyon. 2024 Oct 15. 10(19): e38379
    Daucosterol alleviates heart failure with preserved ejection fraction through activating PPARα pathway.
    Jie Zhou, Bei Wang, Mengyao Wang, Yang Zha, Shengyuan Lu, Feng Zhang, Ying Peng, Yajun Duan, Dingrong Zhong, Shuang Zhang.
      Heart failure with preserved ejection fraction (HFpEF) has been increasing in the population in recent years and is mainly characterized by preserved left ventricle ejection fraction (LVEF), diastolic dysfunction and systemic inflammation. Daucosterol (DAU), a glycoside of β-sitosterol, has good anti-inflammatory and antioxidative properties; however, its effects and mechanisms in HFpEF have not been investigated. To detect whether DAU could alleviate HFpEF, C57BL/6J male mice were fed with N-nitro-l-arginine methyl ester (L-NAME) in drinking water and high fat diet (HFD) and treated with DAU by gavage (i.g.) for 10 weeks. The results showed that DAU treatment significantly alleviated HFpEF in mice. Mechanistically, by controlling PPARα and preventing NF-κB phosphorylation, DAU reduced oxidative stress and the inflammatory response. In conclusion, our study provides a new clue for natural product DAU in alleviating HFpEF.
    Keywords:  Daucosterol; HFpEF; Inflammation; NF-κB; PPARα
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e38379
  59. Therapeutics (Basel). 2024 Sep;1(1): 42-51
    Management of Left Atrial Tachyrhythms in the Setting of HFpEF with Pulsed-Field Ablation: Treating Fire with Water?
    Tyler Chinedu Chinyere, Ikeotunye Royal Chinyere.
      Atrial fibrillation (AF) in the setting of heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent comorbidity and is enabled by adverse left atrial (LA) remodeling, dilation, and scar tissue formation. These changes are facilitated by poor left ventricular compliance. A growing body of clinical evidence and medical guidelines suggest that managing atrial tachyrhythms with catheter ablation (CA) is paramount to treating concomitant HF. This recommendation is complicated in that thermal CA modalities, namely radiofrequency ablation and cryoablation, are both therapeutic via inducing additional scar tissue. AF treatment with thermal CA may compound the atrial scar burden for patients who already have extensive scars secondary to HFpEF. Therefore, thermal CA could act as "gasoline" to the slowly burning "fire" within the LA, increasing the rate of AF recurrence. Pulsed-field ablation (PFA), which utilizes high-voltage irreversible electroporation, is a non-thermal CA technique that is capable of disrupting reentrant microcircuits and arrhythmogenic foci without inducing significant scar burden. PFA has the potential to mitigate the strong fibrosis response to thermal CA that predisposes to AF by serving as "water" rather than "gasoline". Thus, PFA may increase the efficacy and durability of CA for AF in HFpEF, and subsequently, may decrease the risk of procedural complications from repeat CAs. In this article, we provide a summary of the clinical concepts underlying HFpEF and AF and then summarize the data to date on the potential of PFA being a superior CA technique for AF in the setting of comorbid HFpEF.
    Keywords:  atrial fibrillation; catheter; chronic fibrosis; electrophysiology; heart failure; nonthermal
    DOI:  https://doi.org/10.3390/therapeutics1010006
  60. Int J Mol Sci. 2024 Oct 09. pii: 10828. [Epub ahead of print]25(19):
    NBF2, an Algal Fiber-Rich Formula, Reverses Diabetic Dyslipidemia and Hyperglycemia In Vivo.
    Nlandu Roger Ngatu, Akram Hossain, Nao Maruo, Steeve Akumwami, Asadur Md Rahman, Masamitsu Eitoku, Kanae Kanda, Akira Nishiyama, Narufumi Suganuma, Tomohiro Hirao.
      Ulva prolifera, known as Aonori in Japan, is an edible alga species that is mass-cultivated in Japan. Supplementation with Aonori-derived biomaterials has been reported to enhance metabolic health in previous studies. This was an experimental study that evaluated the metabolic health effects of NBF2, a formula made of algal and junos Tanaka citrus-derived biomaterials, on obesity and type 2 diabetes (T2DM). We used 18 obese and hyperglycemic Otsuka Long-Evans Tokushima Fatty (OLETF) rats that were assigned randomly to three groups of six animals: a high-dose NBF2 drink (20 mg/kg) group, a low-dose (10 mg/kg) NBF2 drink group and the control group that received 2 mL of tap water daily for a total of six weeks. We also used eight LETO rats as the normal control group. In addition to the glucose tolerance test (OGTT), ELISA and real-time PCR assays were performed. High-dose and lowdose NBF2 improved insulin sensitivity, as well as glycemic and lipid profiles, as compared with control rats. The OGTT showed that both NBF2 groups and LETO rats had normalized glycemia by the 90-min time-point. NBF2 up-regulated PPARα/γ-mRNA and Sirt2-mRNA gene expressions in BAT and improved the blood pressure profile. These findings suggest that the NBF2 formula, which activates PPAR-α/γ mRNA and Sirt2-mRNA, may reverse dyslipidemia and hyperglycemia in T2DM.
    Keywords:  algal formula; dyslipidemia; hyperglycemia; peroxisome proliferation-activated receptor; sirtuin; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms251910828
  61. Metabolomics. 2024 Oct 13. 20(6): 117
    Nutritional deuterium depletion and health: a scoping review.
    Nicole Korchinsky, Anne M Davis, László G Boros.
       INTRODUCTION: Large variations in fatty and amino acid natural 2H/1H ratios in reference with solvent water point to the active involvement of compartmental, inter- and intramolecular deuterium disequilibrium in adaptive biology. Yet, the human deutenome is an untapped area of energy metabolism and health in humans.
    OBJECTIVES: The purpose of this scoping review is to examine health effects through deuterium homeostasis using deuterium-depleted water and/or a deuterium-depleted diet. We also aim to reveal health effects of nutritional, metabolic and exercise ketosis, i.e. complete mitochondrial fatty acid oxidation with the production of deuterium depleted (deupleted) metabolic water.
    METHODS: A protocol process approach was used to retrieve current research in deuterium depletion according to the preferred reporting items protocol for systematic reviews and meta-analyses, extension for scoping reviews with checklist (PRISMA-ScR).
    RESULTS: Fifteen research articles were used. All retrieved articles were heterogenous in nature and additional themes did not evolve. Deuterium depletion was found to have beneficial health effects in the following conditions: cancer prevention, cancer treatment, depression, diabetes, long-term memory, anti-aging, and sports performance. Deutenomics is actively pursued in drug research and there are biomarker roles attributed to large natural variations with adaptive significance in biology.
    CONCLUSION: Even with limited data, consistent deuterium depletion can be seen across all conditions reviewed. More randomized control trials are recommended to confirm cause and effect for translationally and clinically informed integrative nutrition-based medical interventions.
    Keywords:  Cancer; Deutenomics; Diabetes; Health; Human deutenome project; Ketogenic diet; Metabolic water; Mitochondria; Nutrition
    DOI:  https://doi.org/10.1007/s11306-024-02173-4
  62. Skelet Muscle. 2024 Oct 18. 14(1): 24
    Metabolic pathways for removing reactive aldehydes are diminished in the skeletal muscle during heart failure.
    Mamata Chaudhari, Igor Zelko, Pawel Lorkiewicz, David Hoetker, Yibing Nong, Benjamin Doelling, Kenneth Brittian, Aruni Bhatnagar, Sanjay Srivastava, Shahid P Baba.
      Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways. Whether the formation of lipid peroxidation products and metabolic pathways that remove these toxic products are affected during heart failure-associated skeletal muscle wasting has never been studied. Male C57BL/6J mice were subjected to sham and transverse aortic constriction (TAC) surgeries for 4, 8 or 14 weeks. Different skeletal muscle beds were weighed, and the total cross-sectional area of the gastrocnemius muscle was measured via immunohistochemistry. Muscle function and muscle stiffness were measured by a grip strength meter and atomic force microscope, respectively. Atrophic and inflammatory marker levels were measured via qRT‒PCR. The levels of acrolein and HNE-protein adducts, aldehyde-removing enzymes, the histidyl dipeptide-synthesizing enzyme carnosine synthase (CARNS), and amino acid transporters in the gastrocnemius muscle were measured via Western blotting and qRT‒PCR. Histidyl dipeptides and histidyl dipeptide aldehyde conjugates in the Gastrocnemius and soleus muscles were analyzed by LC/MS-MS. Body weight, gastrocnemius muscle and soleus muscle weights and the total cross-sectional area of the gastrocnemius muscle were decreased after 14 weeks of TAC. Heart weight, cardiac function, grip strength and muscle stiffness were decreased in the TAC-operated mice. Expression of the atrophic and inflammatory markers Atrogin1 and TNF-α, respectively, was increased ~ 1.5-2fold in the gastrocnemius muscle after 14 weeks of TAC (p < 0.05 and p = 0.004 vs sham). The formation of HNE and acrolein protein adducts was increased, and the expression of the aldehyde-removing enzyme aldehyde dehydrogenase (ALDH2) was decreased in the gastrocnemius muscle of TAC mice. Carnosine (sham: 5.76 ± 1.3 vs TAC: 4.72 ± 0.7 nmol/mg tissue, p = 0.04) and total histidyl dipeptide levels (carnosine and anserine; sham: 11.97 ± 1.5 vs TAC: 10.13 ± 1.4 nmol/mg tissue, p < 0.05) were decreased in the gastrocnemius muscle of TAC mice. Depletion of histidyl dipeptides diminished the aldehyde removal capacity of the atrophic gastrocnemius muscle. Furthermore, CARNS and TAUT protein expression were decreased in the atrophic gastrocnemius muscle. Our data reveals that reduced expression of ALDH2 and depletion of histidyl dipeptides in the gastrocnemius muscle during heart failure leads to the accumulation of toxic aldehydes and might contribute to muscle wasting.
    Keywords:  Anserine; Atrophy; Autophagy ; Heart failure; Muscle wasting; Ubiquitin‒proteasome pathway
    DOI:  https://doi.org/10.1186/s13395-024-00354-2
  63. Exp Physiol. 2024 Oct 18.
    Skeletal muscle fuel utilisation during exercise: A historical account of the Scandinavian involvement in the 'Zuntz-Chauveau controversy'.
    Ronan M G Berg.
      
    DOI:  https://doi.org/10.1113/EP092156
  64. Br J Nutr. 2024 Oct 18. 1-8
    Associations of artificial sweetener intake with cardiometabolic disorders and mortality: a population-based study.
    Jun-Yan Kan, Dong-Chen Wang, Yu Chang, Zi-Hao Jiang, Xiao-Min Jiang, Hao Xie, Xin-Xin Jia, Ming-Xing Chen, Yue Gu.
      Artificial sweeteners are generally used and recommended to alternate added sugar for health promotion. However, the health effects of artificial sweeteners remain unclear. In this study, we included 6371 participants from the National Health and Nutrition Examination Survey with artificial sweetener intake records. Logistic regression and Cox regression were applied to explore the associations between artificial sweeteners and risks of cardiometabolic disorders and mortality. Mendelian randomisation was performed to verify the causal associations. We observed that participants with higher consumption of artificial sweeteners were more likely to be female and older and have above medium socio-economic status. After multivariable adjustment, frequent consumers presented the OR (95 % CI) for hypertension (1·52 (1·29, 1·80)), hypercholesterolaemia (1·28 (1·10, 1·50)), diabetes (3·74 (3·06, 4·57)), obesity (1·52 (1·29, 1·80)), congestive heart failure (1·89 (1·35, 2·62)) and heart attack (1·51 (1·10, 2·04)). Mendelian randomisation confirmed the increased risks of hypertension and type 2 diabetes. Moreover, an increased risk of diabetic mortality was identified in participants who had artificial sweeteners ≥ 1 daily (HR = 2·62 (1·46, 4·69), P = 0·001). Higher consumption of artificial sweeteners is associated with increased risks of cardiometabolic disorders and diabetic mortality. These results suggest that using artificial sweeteners as sugar substitutes may not be beneficial.
    Keywords:  Artificial sweetener; CVD; Diabetic mortality; National Health and Nutrition Examination Survey; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1017/S000711452400223X
  65. J Clin Med. 2024 Sep 24. pii: 5685. [Epub ahead of print]13(19):
    Heart Failure with Preserved Ejection Fraction Correlates with Fibrotic Atrial Myopathy in Patients Undergoing Atrial Fibrillation Ablation.
    Jonghui Lee, Michael Sponder, Stefan Stojkovic, Martin Riesenhuber, Andreas Hammer, Thomas M Hofbauer, Patrick Sulzgruber, Stefanie Burger, Stefan Kastl, Franz Duca, Robert Schönbauer.
      Background: The incidence of atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) is high. Impaired left atrial (LA) function is a major determinant in HFpEF. However, the extent of electrical LA tissue degeneration in HFpEF is unknown. Therefore, we sought to investigate the amount of arrhythmogenic and fibrotic LA tissue degeneration in HFpEF patients presenting for AF ablation. Methods: We prospectively screened consecutive patients presenting for first time AF ablation. The HFA-PEFF score was used to identify HFpEF patients. Bipolar high-density voltage mapping was created in sinus rhythm prior to ablation to evaluate the general LA bipolar voltage and quantify areas of low voltage. LVAs were defined as areas with bipolar voltage < 0.5 mV. Results: In total, 187 patients were prospectively enrolled (age 65 ± 11 years, 45% female, 46% persistent AF, 25% HFpEF) in this study. HFpEF patients were older and had a higher CHA2DS2-VASc score (70 ± 9 vs. 63 ± 11 years and 3.2 ± 1.5 vs. 2.3 ± 1.5, each p < 0.001, respectively). Overall, low-voltage areas (LVAs) were present in 97 patients (52%), whereas 76% of the HFpEF population had LVA, as compared to 44% of patients without HFpEF (p < 0.001). HFpEF was associated with generally decreased LA bipolar voltage (1.09 ± 0.64 vs. 1.83 ± 0.91 mV; p < 0.001) and predictive of the presence of low-voltage areas (76% vs. 44% p < 0.001). The HFA-PEFF score inversely correlated with LA bipolar voltage (=-0.454; p < 0.001). Conclusions: HFpEF closely relates to generally decreased LA bipolar voltage and to the existence of fibrotic and arrhythmogenic LA tissue degeneration.
    Keywords:  HFpEF; atrial fibrillation; atrial myopathy
    DOI:  https://doi.org/10.3390/jcm13195685
  66. Exp Eye Res. 2024 Oct 11. pii: S0014-4835(24)00346-4. [Epub ahead of print] 110124
    Hyperglycemia-depleted glutamine contributes to the pathogenesis of diabetic corneal endothelial dysfunction.
    Mengmeng Yu, Huilin Chen, Chen Chen, Can Zhao, Qingjun Zhou, Lixin Xie, Ting Wang.
      Diabetic mellitus causes various complications, including the corneal endothelial dysfunction (CED) that leads to corneal edema and vision loss, especially in the DM patients with intraocular surgeries. However, the pathogenic mechanism of hyperglycemia-caused CED remains incomplete understood. Here we firstly screened and identified the glutamine contents of anterior humor were significantly reduced in both the type 2 diabetic patients and streptozotocin-induced type 1 diabetic mice. To explore the potential therapeutic effects of glutamine supplement on the protection of diabetic corneal endothelial dysfunction, we performed the anterior chamber perfusion with the addition of L-alanyl-L-glutamine (Ala-Gln), and confirmed that Ala-Gln supplement not only accelerated the resolution of corneal edema and recovery of corneal thickness, but also preserved the regular arrangement and barrier-pomp function of corneal. Mechanistically, we revealed that the supplements of Ala-Gln protect corneal endothelial cells from the deleterious effects of high glucose-induced oxidative stress, mitochondrial dysfunction, and cell apoptosis. Overall, these results indicate the glutamine depletion plays an important role in the diabetic corneal endothelial dysfunction, while the Ala-Gln supplement during intraocular surgery provide an effective prevention strategy through regulating the redox homeostasis and mitochondrial function of corneal endothelial cells.
    Keywords:  Diabetes; corneal endothelium; glutamine; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.exer.2024.110124
  67. Nutrients. 2024 Sep 28. pii: 3296. [Epub ahead of print]16(19):
    Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target?
    Daniel Foran, Charalambos Antoniades, Ioannis Akoumianakis.
      Cardiovascular disease is a leading cause of morbidity and mortality. New research elucidates increasingly complex relationships between cardiac and metabolic health, giving rise to new possible therapeutic targets. Sphingolipids are a heterogeneous class of bioactive lipids with critical roles in normal human physiology. They have also been shown to play both protective and deleterious roles in the pathogenesis of cardiovascular disease. Ceramides are implicated in dysregulating insulin signalling, vascular endothelial function, inflammation, oxidative stress, and lipoprotein aggregation, thereby promoting atherosclerosis and vascular disease. Ceramides also advance myocardial disease by enhancing pathological cardiac remodelling and cardiomyocyte death. Glucosylceramides similarly contribute to insulin resistance and vascular inflammation, thus playing a role in atherogenesis and cardiometabolic dysfunction. Sphingosing-1-phosphate, on the other hand, may ameliorate some of the pathological functions of ceramide by protecting endothelial barrier integrity and promoting cell survival. Sphingosine-1-phosphate is, however, implicated in the development of cardiac fibrosis. This review will explore the roles of sphingolipids in vascular, cardiac, and metabolic pathologies and will evaluate the therapeutic potential in targeting sphingolipids with the aim of prevention and reversal of cardiovascular disease in order to improve long-term cardiovascular outcomes.
    Keywords:  atherosclerosis; cardiovascular disease; ceramide; heart failure; inflammation; sphingolipid; sphingomyelin
    DOI:  https://doi.org/10.3390/nu16193296
  68. Int J Mol Sci. 2024 Oct 01. pii: 10597. [Epub ahead of print]25(19):
    Readdressing the Localization of Apolipoprotein E (APOE) in Mitochondria-Associated Endoplasmic Reticulum (ER) Membranes (MAMs): An Investigation of the Hepatic Protein-Protein Interactions of APOE with the Mitochondrial Proteins Lon Protease (LONP1), Mitochondrial Import Receptor Subunit TOM40 (TOMM40) and Voltage-Dependent Anion-Selective Channel 1 (VDAC1).
    Johanna Rueter, Gerald Rimbach, Stephanie Bilke, Andreas Tholey, Patricia Huebbe.
      As a component of circulating lipoproteins, APOE binds to cell surface receptors mediating lipoprotein metabolism and cholesterol transport. A growing body of evidence, including the identification of a broad variety of cellular proteins interacting with APOE, suggests additional independent functions. Investigating cellular localization and protein-protein interactions in cultured human hepatocytes, we aimed to contribute to the elucidation of hitherto unnoted cellular functions of APOE. We observed a strong accumulation of APOE in MAMs, equally evident for the two major isoforms APOE3 and APOE4. Using mass spectrometry proteome analyses, novel and previously noted APOE interactors were identified, including the mitochondrial proteins TOMM40, LONP1 and VDAC1. All three interactors were present in MAM fractions, which we think initially facilitates interactions with APOE. LONP1 is a protease with chaperone activity, which migrated to MAMs in response to ER stress, displaying a reinforced interaction with APOE. We therefore hypothesize that APOE may help in the unfolded protein response (UPR) by acting as a co-chaperone in cooperation with LONP1 at the interface of mitochondria and ER membranes. The interaction of APOE with the integral proteins TOMM40 and VDAC1 may point to the formation of bridging complexes connecting mitochondria with other organelles.
    Keywords:  APOE4; chaperone; co-immunoprecipitation; liver; mitochondria–ER contacts; stress response; thapsigargin
    DOI:  https://doi.org/10.3390/ijms251910597
  69. Nature. 2024 Oct 16.
    Quantifying constraint in the human mitochondrial genome.
    Nicole J Lake, Kaiyue Ma, Wei Liu, Stephanie L Battle, Kristen M Laricchia, Grace Tiao, Daniela Puiu, Kenneth K Ng, Justin Cohen, Alison G Compton, Shannon Cowie, John Christodoulou, David R Thorburn, Hongyu Zhao, Dan E Arking, Shamil R Sunyaev, Monkol Lek.
      Mitochondrial DNA (mtDNA) has an important yet often overlooked role in health and disease. Constraint models quantify the removal of deleterious variation from the population by selection and represent powerful tools for identifying genetic variation that underlies human phenotypes1-4. However, nuclear constraint models are not applicable to mtDNA, owing to its distinct features. Here we describe the development of a mitochondrial genome constraint model and its application to the Genome Aggregation Database (gnomAD), a large-scale population dataset that reports mtDNA variation across 56,434 human participants5. Specifically, we analyse constraint by comparing the observed variation in gnomAD to that expected under neutrality, which was calculated using a mtDNA mutational model and observed maximum heteroplasmy-level data. Our results highlight strong depletion of expected variation, which suggests that many deleterious mtDNA variants remain undetected. To aid their discovery, we compute constraint metrics for every mitochondrial protein, tRNA and rRNA gene, which revealed a range of intolerance to variation. We further characterize the most constrained regions within genes through regional constraint and identify the most constrained sites within the entire mitochondrial genome through local constraint, which showed enrichment of pathogenic variation. Constraint also clustered in three-dimensional structures, which provided insight into functionally important domains and their disease relevance. Notably, we identify constraint at often overlooked sites, including in rRNA and noncoding regions. Last, we demonstrate that these metrics can improve the discovery of deleterious variation that underlies rare and common phenotypes.
    DOI:  https://doi.org/10.1038/s41586-024-08048-x
  70. BMC Cardiovasc Disord. 2024 Oct 16. 24(1): 562
    Cardiac structural and functional changes in OSAHS patients with heart failure with preserved ejection fraction and atrial fibrillation.
    Huaqing Wei, Yan Luo, Cen Wei, Huixian Liao, Fengying Nong.
       OBJECTIVE: To explore the cardiac structural and functional changes in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF).
    METHODS: This retrospective study included 336 OSAHS patients with HFpEF. They were divided into Groups A (without an AF history and no AF episodes during cardiac color ultrasound examination), B (an AF history but no AF episodes), and C (an AF history and AF episodes). They all received cardiac color ultrasound examinations. Cardiac structural and functional changes in ultrasonic cardiograms were compared between the three groups.
    RESULTS: Compared with Groups A and B, Group C showed increased left atrial diameter (LAD), left atrial volume (LAV), right ventricular diameter at end-diastole (RV-D1), right ventricular diameter at end-systole (RV-D2), right ventricular outflow tract diameter (RVOT2), right atrial diameter at end-diastole (RA-D1), right atrial diameter at end-systole (RA-D2), and right atrial area (RAA) (p < 0.05). Compared with Group A, Group C showed decreased fractional shortening (FS), left ventricular ejection fraction (LVEF), deceleration time (DT), isovolumic relaxation time (IVRT), E/E' ratio, and peak filling velocity (FPV), as well as increased E and E' (p < 0.01). Compared with Group B, Group C showed decreased FS and increased E and FPV (p < 0.01).
    CONCLUSION: In OSAHS patients with HFpEF and AF, cardiac remodeling and AF incidence are increased with the severity of OSAHS. OSAHS patients with HFpEF combined with AF have a significantly higher abnormality rate in right heart structural indices rather than left heart, mainly in the right atrium.
    Keywords:  Atrial fibrillation; Heart failure with preserved ejection fraction; Heart structure; Obstructive sleep apnea-hypopnea syndrome; Ultrasonic cardiogram
    DOI:  https://doi.org/10.1186/s12872-024-04217-y
  71. Clin Nutr. 2024 Oct 11. pii: S0261-5614(24)00373-X. [Epub ahead of print]43(12): 36-47
    Metabolic kinetics and muscle and brain health markers in older adults, and the role of age and presence of chronic morbidities: A large cross-sectional cohort study.
    Minchae C Kang, Nicolaas E P Deutz, Sarah K Kirschner, Mariëlle P K J Engelen.
       BACKGROUND & AIMS: Older adults are at risk for muscle and cognitive function decline during advanced aging, but the underlying metabolic mechanisms and the role of aging-associated chronic morbidities remain unclear. In the present study, we examined whether protein and amino acid kinetics in older adults with and without chronic morbidities are different when 50-70 and 70-90 of age and related to markers of muscle and brain health declines.
    METHODS: In a large cross-sectional observational study, 575 older adults from 12 trials (2014-2022) were stratified based on their age (50-70y vs. 70-95y) and the presence of chronic morbidities. The main outcomes were whole-body production (WBP) and interconversions of amino acids by stable amino acid tracers, body composition, and muscle and cognitive performance. Additionally, the association between metabolic markers and muscle and brain health was assessed.
    RESULTS: Overall lower muscle strength, muscle and fat mass, and cognitive function (p < 0.03), but no mood disturbances, were found in 70-95y compared to 50-70y older adults. Presence of morbidities was associated with lower muscle strength and mass, and cognitive function, but higher visceral adipose tissue, and mood disturbances (p < 0.05). Aging was associated with suppressed WBP of most amino acids, de novo arginine production, and net protein breakdown, but higher myofibrillar protein breakdown (p < 0.007). Presence of morbidities was associated with lower WBP of glutamine, glutamate, histidine, isoleucine, phenylalanine, tyrosine, and net protein breakdown, and higher WBP of valine and taurine (p < 0.04). Age showed significant negative correlations with WBP of nearly all amino acids, de novo arginine production and net protein breakdown (r: [-0.407, -0.136], p < 0.01) but a positive correlation with WBP of myofibrillar protein breakdown (r = 0.133, p = 0.009). Lean mass showed positive correlations with de novo arginine production and net protein breakdown and WBP of all amino acids except for isoleucine (r: [0.16, 0.799], p < 0.005). MoCA showed a positive correlation with WBP of leucine and valine (r: [0.163, 0.2], p < 0.03). Worse cognitive performance was positively associated with WBP of tau-methylhistidine and taurine (r: [0.13, 0.141], p < 0.04), but negatively associated with WBP of glycine and valine, de novo arginine production, and net protein breakdown (r: [-0.222, -0.115], p < 0.05).
    CONCLUSION: Comprehensive phenotyping of a large group of older adults revealed differences in metabolic health in response to advanced aging and chronic morbidities. Poor muscle health accompanied by advanced aging was associated with overall metabolic downregulation, except for enhanced myofibrillar (muscle) protein breakdown. Presence of chronic morbidities was further associated with disturbed muscle health, mood, arginine, and taurine pathways, and higher visceral adipose tissue. Therefore, different phenotypes among older adults need to be considered when evaluating therapeutic approaches to improve muscle and brain health.
    Keywords:  Aging; Cognitive aging; Metabolism; Protein and amino acid kinetics; Sarcopenia; Stable isotope tracers
    DOI:  https://doi.org/10.1016/j.clnu.2024.10.015
  72. J Exp Biol. 2024 Oct 15. pii: jeb249348. [Epub ahead of print]227(20):
    The integrative biology of the heart: mechanisms enabling cardiac plasticity.
    William Joyce, Holly A Shiels, Craig E Franklin.
      Cardiac phenotypic plasticity, the remodelling of heart structure and function, is a response to any sustained (or repeated) stimulus or stressor that results in a change in heart performance. Cardiac plasticity can be either adaptive (beneficial) or maladaptive (pathological), depending on the nature and intensity of the stimulus. Here, we draw on articles published in this Special Issue of Journal of Experimental Biology, and from the broader comparative physiology literature, to highlight the core components that enable cardiac plasticity, including structural remodelling, excitation-contraction coupling remodelling and metabolic rewiring. We discuss when and how these changes occur, with a focus on the underlying molecular mechanisms, from the regulation of gene transcription by epigenetic processes to post-translational modifications of cardiac proteins. Looking to the future, we anticipate that the growing use of -omics technologies in integration with traditional comparative physiology approaches will allow researchers to continue to uncover the vast scope for plasticity in cardiac function across animals.
    Keywords:  Calcium; Cardiovascular; Heart; Hypertrophy; Mitochondria; Sarcomere
    DOI:  https://doi.org/10.1242/jeb.249348
  73. Am J Physiol Gastrointest Liver Physiol. 2024 Oct 15.
    Alterations in cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation.
    Michael Momoh, Sudiksha Rathan-Kumar, Andreanna Burman, Monica E Brown, Francisca Adeniran, Cynthia Ramos, James R Goldenring, Joseph T Roland, Izumi Kaji.
      Functional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice, Vil1-CreERT2;Myo5bflox/flox (MYO5B∆IEC) and Vil1-CreERT2;Myo5bflox/G519R (MYO5B(G519R)), we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5B∆IEC small intestine. Consistent with these observations in vivo, RNA-sequencing of enteroids generated from the two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5B∆IEC tissues and enteroids. The present study demonstrated that the highly soluble LPAR5-preferred agonist, Compound-1, improved sodium transporter localization and absorptive function, and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on intestine with MYO5B functional loss through epithelial cell-autonomous pathways that can accelerate the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for treatment of MVID symptoms induced by different point mutations in MYO5B.
    Keywords:  Enteroid; Lysophosphatidic acid receptor; Microvillus inclusion disease; Mitochondria; Mouse model
    DOI:  https://doi.org/10.1152/ajpgi.00091.2024
  74. Diabetes Obes Metab. 2024 Oct 17.
    Low-calorie, high-protein diets, regardless of protein source, improve glucose metabolism and cardiometabolic profiles in subjects with prediabetes or type 2 diabetes and overweight or obesity.
    Carmen Rodrigo-Carbó, Loreto Madinaveitia-Nisarre, Sofía Pérez-Calahorra, Irene Gracia-Rubio, Alberto Cebollada, Carlos Galindo-Lalana, Rocío Mateo-Gallego, Itziar Lamiquiz-Moneo.
       AIM: The aim was to study the effect of two low-calorie, high-protein (HP) diets, with most of the protein coming from animal or plant sources, on glycaemic and other cardiometabolic outcomes in subjects with overweight or obesity and glucose metabolism disorders.
    MATERIALS AND METHODS: A total of 117 participants aged >18 years with body mass index over 27.5 kg/m2 and prediabetes or type 2 diabetes mellitus (T2DM) were randomized to one of two HP low-calorie diets (35% of total calories from protein), in which 75% of the protein was from either plant-based sources (HPP) or animal sources (HPA). For both diets, 30% and 35% of the total calories were from fat and carbohydrates, respectively. The dietary intervention lasted 6 months.
    RESULTS: Both diets improved body composition to a similar extent, including weight loss (-8.05 ± 5.12 kg for the HPA diet and -7.70 ± 5.47 kg for the HPP diet at 6 months) and fat mass, mainly visceral fat. Both diets had a similar beneficial effect on glucose metabolism, including fasting glucose, insulin, homeostasis model assessment of insulin resistance index and glycated haemoglobin. Other biochemical parameters, including lipid profiles, liver enzymes, adipokines and inflammatory biomarkers, similarly improved in both groups. Fasting incretins, mainly glucagon-like peptide 1, decreased significantly in both groups, and this effect correlated with weight loss.
    CONCLUSIONS: Low-calorie HP diets improved body composition, glucose metabolism and other cardiometabolic outcomes, regardless of protein source (either animal or plant sources), in outpatients with prediabetes or T2DM.
    CLINICAL TRIAL REGISTRATION: The clinical trial was registered in ClinicalTrials.gov (identifier: NCT05456347) https://clinicaltrials.gov/study/NCT05456347?term=NCT05456347&rank=1.
    Keywords:  animal protein; diet; obesity; plant protein; type 2 diabetes
    DOI:  https://doi.org/10.1111/dom.16013
  75. Commun Biol. 2024 Oct 17. 7(1): 1342
    Protein kinase 2 of the giant sarcomeric protein UNC-89 regulates mitochondrial morphology and function.
    Yohei Matsunaga, Hiroshi Qadota, Nasab Ghazal, Leila Lesanpezeshki, Till Dorendorf, Jasmine C Moody, Arnaud Ahier, Courtney J Matheny, Siva A Vanapalli, Steven Zuryn, Olga Mayans, Jennifer Q Kwong, Guy M Benian.
      UNC-89 is a giant sarcomeric M-line protein required for sarcomere organization and optimal muscle function. UNC-89 contains two protein kinase domains, PK1 and PK2, separated by an elastic region. Here we show that PK2 is a canonical kinase expected to be catalytically active. C. elegans expressing UNC-89 with a lysine to alanine (KtoA) mutation to inactivate PK2 have normally organized sarcomeres and SR, and normal muscle function. PK2 KtoA mutants have fragmented mitochondria, correlated with more mitochondrially-associated DRP-1. PK2 KtoA mutants have increased ATP levels, increased glycolysis and altered levels of electron transport chain complexes. Muscle mitochondria show increased complex I and decreased complex II basal respiration, each of which cannot be uncoupled. This suggests that mutant mitochondria are already uncoupled, possibly resulting from an increased level of the uncoupling protein, UCP-4. Our results suggest signaling from sarcomeres to mitochondria, to help match energy requirements with energy production.
    DOI:  https://doi.org/10.1038/s42003-024-07042-3
  76. Obesity (Silver Spring). 2024 Oct 13.
    Decoding visceral adipose tissue molecular signatures in obesity and insulin resistance: a multi-omics approach.
    Dipayan Roy, Raghumoy Ghosh, Ritwik Ghosh, Manoj Khokhar, Ma Yin Yin Naing, Julián Benito-León.
       OBJECTIVE: Obesity-associated insulin resistance (IR) is responsible for considerable morbidity and mortality globally. Despite vast genomic data, many areas, from pathogenesis to management, still have significant knowledge gaps. We aimed to characterize visceral adipose tissue (VAT) in obesity and IR through a multi-omics approach.
    METHODS: We procured data on VAT samples from the Gene Expression Omnibus (GEO) for the following two groups: 1) populations with obesity (n = 34) versus those without (n = 26); and 2) populations with obesity and IR (n = 15) versus those with obesity but without IR (n = 15). Gene set enrichment, protein-protein interaction network construction, hub gene identification, and drug-gene interactions were performed, followed by regulatory network prediction involving transcription factors (TFs) and microRNAs (miRNAs).
    RESULTS: Interleukin signaling pathways, cellular differentiation, and regulation of immune response revealed a significant cross talk between VAT and the immune system. Other findings include cancer pathways, neurotrophin signaling, and aging. A total of 10 hub genes, i.e., STAT1, KLF4, DUSP1, EGR1, FOS, JUN, IL2, IL6, MMP9, and FGF9, 24 TFs, and approved hub gene-targeting drugs were obtained. A total of 10 targeting miRNAs (e.g., hsa-miR-155-5p, hsa-miR-34a-5p) were associated with obesity and IR-related pathways.
    CONCLUSIONS: Our multi-omics integration method revealed hub genes, TFs, and miRNAs that can be potential targets for investigation in VAT-related inflammatory processes and IR, therapeutic management, and risk stratifications.
    DOI:  https://doi.org/10.1002/oby.24146
  77. Sovrem Tekhnologii Med. 2024 ;16(1): 54-64
    Sphingomyelins of Local Fat Depots and Blood Serum as Promising Biomarkers of Cardiovascular Diseases.
    E V Belik, Yu A Dyleva, E G Uchasova, S V Ivanov, A N Stasev, M G Zinets, O V Gruzdeva.
      Assessment of the blood lipid spectrum does not always properly reflect local dysfunctional changes in the adipose tissue and prevents identification of all patients at high risk of cardiovascular diseases (CVD). Monitoring of changes in sphingomyelin levels allows to assess and anticipate the development and/or severity of these diseases, as well as to make sphingomyelins new therapeutic targets. The aim of the study was to evaluate the sphingomyelin spectrum of local fat depots and blood serum in connection with clinical and instrumental indicators in patients with coronary artery disease (CAD) and patients with degenerative acquired valvular heart disease (AVHD).
    Materials and Methods: The study analyzed samples of subcutaneous, epicardial, perivascular adipose tissue (SAT, EAT, PVAT, respectively) received from 30 patients with CAD and 30 patients with AVHD. Sphingomyelin spectrum of the blood serum was assessed using a high-resolution chromatography-mass spectrometric complex (liquid chromatograph of the Agilent 1200 series (Agilent Technologies, USA) with a maXis impact mass spectrometric detector (Bruker Daltonics, Germany)). Determination of the levels of sphingomyelins (SM) in adipose tissue samples was conducted by high performance liquid chromatography with mass spectrometric detection in the mass/charge ratio range from 100 to 1700.
    Results: Consistent sphingomyelin spectrum of local fat depots and blood serum was revealed in CAD and AVHD. However, the content of SM varied: in CAD, a specific enhancement of SM in epicardial adipose tissue was observed compared to subcutaneous and perivascular localization. In AVHD, PVAT was characterized by a statistically significant increase in the levels of all SM relative to EAT. Almost all measured SM types in the serum of patients with CAD were higher than the levels in the AVHD group.
    Conclusion: Established associations of indicators of the sphingomyelin profile of adipose tissue and blood serum with clinical and instrumental indicators in CVD indicate the relationship between the metabolism of SM in adipose tissue of cardiac localization and disorders of systolic and diastolic function of the LV in patients with CVD, multivessel coronary disease in CAD and allow the use of SM as promising biomarkers of CVD. However, further research is needed to clarify the nature of these relationships.
    Keywords:  acquired degenerative valvular heart disease; coronary artery disease; epicardial adipose tissue; perivascular adipose tissue; sphingomyelin
    DOI:  https://doi.org/10.17691/stm2024.16.1.06
  78. Nat Metab. 2024 Oct 15.
    Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
      
    DOI:  https://doi.org/10.1038/s42255-024-01152-2
  79. Eur Heart J Cardiovasc Imaging. 2024 Oct 14. pii: jeae264. [Epub ahead of print]
    Sex differences in the relationship between body composition and cardiac structure and function.
    Heidi S Hartman, Eunyoung Kim, Salvatore Carbone, Caleb H Miles, Muredach P Reilly.
       AIMS: The purpose of this study was to characterize sex differences in the relationship between body composition and cardiac structure and function. In secondary analyses, we explored pathophysiologic mediators of these relationships.
    METHODS AND RESULTS: In a cross-sectional analysis of 25,063 UK Biobank participants (54% female, median age 55 years), the sex-specific associations of visceral adipose tissue volume (VAT), appendicular lean mass (ALM), and muscle fat infiltration (MFI) with cardiac magnetic resonance (CMR) measures of cardiac structure and function were assessed using linear regression models. Using causal mediation analysis, 10 biomarkers were explored as mediators of the relationship between adipose depots and cardiac parameters. VAT was associated with increased left ventricular mass (LVM; βwomen = 0.54, βmen = 0.00, pint = 0.01) and wall thickness (βwomen = 0.12, βmen = 0.08, pint<0.001) in women only. A similar sex-specific pattern was observed for MFI effects on LVM (βwomen = 0.44, βmen = 0.03, pint<0.001). ALM was associated with increased LVM and LV volumes in both women and men. In mediation analyses, insulin resistance as measured by triglycerides/high density lipoprotein ratio was a potential partial mediator of VAT effects on chamber dimensions.
    CONCLUSIONS: In the largest and most rigorous analyses of body composition and cardiac parameters to date, we demonstrated that VAT is associated with increased LVM and wall thickness in women but not in men. MFI association with cardiac parameters was similar to VAT, significant in women but not in men.
    Keywords:  cardiac magnetic resonance; lean body mass; left ventricular function; left ventricular geometry; visceral adiposity
    DOI:  https://doi.org/10.1093/ehjci/jeae264
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